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1
Kishimoto, Mai, Kentaro Uemura, Takao Sanaki, Akihiko Sato, William W. Hall, Hiroaki Kariwa, Yasuko Orba, Hirofumi Sawa, and Michihito Sasaki. "TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein." Viruses 13, no. 3 (February 28, 2021): 384. http://dx.doi.org/10.3390/v13030384.
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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) utilizes host proteases, including a plasma membrane-associated transmembrane protease, serine 2 (TMPRSS2) to cleave and activate the virus spike protein to facilitate cellular entry. Although TMPRSS2 is a well-characterized type II transmembrane serine protease (TTSP), the role of other TTSPs on the replication of SARS-CoV-2 remains to be elucidated. Here, we have screened 12 TTSPs using human angiotensin-converting enzyme 2-expressing HEK293T (293T-ACE2) cells and Vero E6 cells and demonstrated that exogenous expression of TMPRSS11D and TMPRSS13 enhanced cellular uptake and subsequent replication of SARS-CoV-2. In addition, SARS-CoV-1 and SARS-CoV-2 share the same TTSPs in the viral entry process. Our study demonstrates the impact of host TTSPs on infection of SARS-CoV-2, which may have implications for cell and tissue tropism, for pathogenicity, and potentially for vaccine development.
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Sarker, Jyotirmoy, Pritha Das, Sabarni Sarker, Apurba Kumar Roy, and A. Z. M. Ruhul Momen. "A Review on Expression, Pathological Roles, and Inhibition of TMPRSS2, the Serine Protease Responsible for SARS-CoV-2 Spike Protein Activation." Scientifica 2021 (July 24, 2021): 1–9. http://dx.doi.org/10.1155/2021/2706789.
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SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, uses the host cell membrane receptor angiotensin-converting enzyme 2 (ACE2) for anchoring its spike protein, and the subsequent membrane fusion process is facilitated by host membrane proteases. Recent studies have shown that transmembrane serine protease 2 (TMPRSS2), a protease known for similar role in previous coronavirus infections, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS), is responsible for the proteolytic cleavage of the SARS-CoV-2 spike protein, enabling host cell fusion of the virus. TMPRSS2 is known to be expressed in the epithelial cells of different sites including gastrointestinal, respiratory, and genitourinary system. The infection site of the SARS-CoV-2 correlates with the coexpression sites of ACE2 and TMPRSS2. Besides, age-, sex-, and comorbidity-associated variation in infection rate correlates with the expression rate of TMPRSS2 in those groups. These findings provide valid reasons for the assumption that inhibiting TMPRSS2 can have a beneficial effect in reducing the cellular entry of the virus, ultimately affecting the infection rate and case severity. Several drug development studies are going on to develop potential inhibitors of the protease, using both conventional and computational approaches. Complete understanding of the biological roles of TMPRSS2 is necessary before such therapies are applied.
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Matsuyama, Shutoku, Noriyo Nagata, Kazuya Shirato, Miyuki Kawase, Makoto Takeda, and Fumihiro Taguchi. "Efficient Activation of the Severe Acute Respiratory Syndrome Coronavirus Spike Protein by the Transmembrane Protease TMPRSS2." Journal of Virology 84, no. 24 (October 6, 2010): 12658–64. http://dx.doi.org/10.1128/jvi.01542-10.
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ABSTRACT The distribution of the severe acute respiratory syndrome coronavirus (SARS-CoV) receptor, an angiotensin-converting enzyme 2 (ACE2), does not strictly correlate with SARS-CoV cell tropism in lungs; therefore, other cellular factors have been predicted to be required for activation of virus infection. In the present study, we identified transmembrane protease serine 2 (TMPRSS2), whose expression does correlate with SARS-CoV infection in the upper lobe of the lung. In Vero cells expressing TMPRSS2, large syncytia were induced by SARS-CoV infection. Further, the lysosome-tropic reagents failed to inhibit, whereas the heptad repeat peptide efficiently inhibited viral entry into cells, suggesting that TMPRSS2 affects the S protein at the cell surface and induces virus-plasma membrane fusion. On the other hand, production of virus in TMPRSS2-expressing cells did not result in S-protein cleavage or increased infectivity of the resulting virus. Thus, TMPRSS2 affects the entry of virus but not other phases of virus replication. We hypothesized that the spatial orientation of TMPRSS2 vis-a-vis S protein is a key mechanism underling this phenomenon. To test this, the TMPRSS2 and S proteins were expressed in cells labeled with fluorescent probes of different colors, and the cell-cell fusion between these cells was tested. Results indicate that TMPRSS2 needs to be expressed in the opposing (target) cell membrane to activate S protein rather than in the producer cell, as found for influenza A virus and metapneumoviruses. This is the first report of TMPRSS2 being required in the target cell for activation of a viral fusion protein but not for the S protein synthesized in and transported to the surface of cells. Our findings suggest that the TMPRSS2 expressed in lung tissues may be a determinant of viral tropism and pathogenicity at the initial site of SARS-CoV infection.
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Ramezanpour, Mahnaz, Harrison Bolt, Karen Hon, George Spyro Bouras, Alkis James Psaltis, Peter-John Wormald, and Sarah Vreugde. "Cytokine-Induced Modulation of SARS-CoV2 Receptor Expression in Primary Human Nasal Epithelial Cells." Pathogens 10, no. 7 (July 5, 2021): 848. http://dx.doi.org/10.3390/pathogens10070848.
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Background: Viral entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) via the spike protein enables endocytosis into host cells using the ACE2 receptor and TMPRSS2. The frequent upper respiratory tract symptoms of COVID-19 and the localization of the virus to the nasopharynx, the most common site of swabbing, indicate that the sinonasal mucosa may play an important role in SARS-CoV2 infection and viral replication. Methods: This paper investigates the presence of ACE2 receptor and TMPRESS2 expression in the primary human nasal epithelial cells (HNECs) from the following: chronic rhinosinusitis without nasal polyps (CRSsNP), CRS with nasal polyps (CRSwNP) and control (non-CRS) patients, and maps the expression changes when exposed to Th1, Th2, Th17-associated cytokines. Results: We found that ACE2 and TMPRSS2 expression was higher in control HNECs than CRSwNP HNECs, and that both ACE2 and TMPRSS2 were downregulated further by Th2 cytokines in CRSwNP HNECs. Conclusions: This indicates an immune dysregulated state of CRSwNP mucosa, which normally contributes to a chronic inflammatory state, and might support an altered susceptibility to SARS-CoV2 infection and transmission.
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Sampson, Alexander Thomas, Jonathan Heeney, Diego Cantoni, Matteo Ferrari, Maria Suau Sans, Charlotte George, Cecilia Di Genova, et al. "Coronavirus Pseudotypes for All Circulating Human Coronaviruses for Quantification of Cross-Neutralizing Antibody Responses." Viruses 13, no. 8 (August 10, 2021): 1579. http://dx.doi.org/10.3390/v13081579.
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The novel coronavirus SARS-CoV-2 is the seventh identified human coronavirus. Understanding the extent of pre-existing immunity induced by seropositivity to endemic seasonal coronaviruses and the impact of cross-reactivity on COVID-19 disease progression remains a key research question in immunity to SARS-CoV-2 and the immunopathology of COVID-2019 disease. This paper describes a panel of lentiviral pseudotypes bearing the spike (S) proteins for each of the seven human coronaviruses (HCoVs), generated under similar conditions optimized for high titre production allowing a high-throughput investigation of antibody neutralization breadth. Optimal production conditions and most readily available permissive target cell lines were determined for spike-mediated entry by each HCoV pseudotype: SARS-CoV-1, SARS-CoV-2 and HCoV-NL63 best transduced HEK293T/17 cells transfected with ACE2 and TMPRSS2, HCoV-229E and MERS-CoV preferentially entered HUH7 cells, and CHO cells were most permissive for the seasonal betacoronavirus HCoV-HKU1. Entry of ACE2 using pseudotypes was enhanced by ACE2 and TMPRSS2 expression in target cells, whilst TMPRSS2 transfection rendered HEK293T/17 cells permissive for HCoV-HKU1 and HCoV-OC43 entry. Additionally, pseudotype viruses were produced bearing additional coronavirus surface proteins, including the SARS-CoV-2 Envelope (E) and Membrane (M) proteins and HCoV-OC43/HCoV-HKU1 Haemagglutinin-Esterase (HE) proteins. This panel of lentiviral pseudotypes provides a safe, rapidly quantifiable and high-throughput tool for serological comparison of pan-coronavirus neutralizing responses; this can be used to elucidate antibody dynamics against individual coronaviruses and the effects of antibody cross-reactivity on clinical outcome following natural infection or vaccination.
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Laporte, Manon, Valerie Raeymaekers, Ria Van Berwaer, Julie Vandeput, Isabel Marchand-Casas, Hendrik-Jan Thibaut, Dominique Van Looveren, et al. "The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways." PLOS Pathogens 17, no. 4 (April 22, 2021): e1009500. http://dx.doi.org/10.1371/journal.ppat.1009500.
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The high transmissibility of SARS-CoV-2 is related to abundant replication in the upper airways, which is not observed for the other highly pathogenic coronaviruses SARS-CoV and MERS-CoV. We here reveal features of the coronavirus spike (S) protein, which optimize the virus towards the human respiratory tract. First, the S proteins exhibit an intrinsic temperature preference, corresponding with the temperature of the upper or lower airways. Pseudoviruses bearing the SARS-CoV-2 spike (SARS-2-S) were more infectious when produced at 33°C instead of 37°C, a property shared with the S protein of HCoV-229E, a common cold coronavirus. In contrast, the S proteins of SARS-CoV and MERS-CoV favored 37°C, in accordance with virus preference for the lower airways. Next, SARS-2-S-driven entry was efficiently activated by not only TMPRSS2, but also the TMPRSS13 protease, thus broadening the cell tropism of SARS-CoV-2. Both proteases proved relevant in the context of authentic virus replication. TMPRSS13 appeared an effective spike activator for the virulent coronaviruses but not the low pathogenic HCoV-229E virus. Activation of SARS-2-S by these surface proteases requires processing of the S1/S2 cleavage loop, in which both the furin recognition motif and extended loop length proved critical. Conversely, entry of loop deletion mutants is significantly increased in cathepsin-rich cells. Finally, we demonstrate that the D614G mutation increases SARS-CoV-2 stability, particularly at 37°C, and, enhances its use of the cathepsin L pathway. This indicates a link between S protein stability and usage of this alternative route for virus entry. Since these spike properties may promote virus spread, they potentially explain why the spike-G614 variant has replaced the early D614 variant to become globally predominant. Collectively, our findings reveal adaptive mechanisms whereby the coronavirus spike protein is adjusted to match the temperature and protease conditions of the airways, to enhance virus transmission and pathology.
7
Al-Kuraishy, Hayder M., Marwa S. Al-Niemi, Nawar R. Hussain, Ali I. Al-Gareeb, and Claire Lugnier. "The potential role of Bromhexine in the management of COVID-19: Decipher and a real game-changer." CURRENT MEDICAL AND DRUG RESEARCH 5, no. 01 (May 25, 2021): 1–4. http://dx.doi.org/10.53517/cmdr.2581-5008.512021212.
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Primary infection of SARS-CoV-2 (novel coronavirus or 2019-nCoV), which leads to Covid-19, targets specific cells, such as nasal, bronchial epithelial and pneumocytes, through the viral structural spike (S) protein that binds to the angiotensin-converting enzyme 2 (ACE2) receptor. Also, type 2 transmembrane serine protease (TMPRSS2) present in the host cell promotes viral uptake by cleaving ACE2 and triggering the SARS-CoV-2 S protein, which facilitates SARS-CoV-2 entry into host cells. One of the TMPRSS2 inhibitors with a greater distribution capacity into the lung tissue is bromhexine hydrochloride which attenuates the entry and proliferation of SARS-CoV-2. Bromhexine is an effective drug in the management and treatment of Covid-19 pneumonia via targeting ACE2/ TMPRSS2 pathway. However, prospective and controlled clinical trials are recommended to confirm this observation.
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Cheng, Fang-Ju, Thanh-Kieu Huynh, Chia-Shin Yang, Dai-Wei Hu, Yi-Cheng Shen, Chih-Yen Tu, Yang-Chang Wu, et al. "Hesperidin Is a Potential Inhibitor against SARS-CoV-2 Infection." Nutrients 13, no. 8 (August 16, 2021): 2800. http://dx.doi.org/10.3390/nu13082800.
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Hesperidin (HD) is a common flavanone glycoside isolated from citrus fruits and possesses great potential for cardiovascular protection. Hesperetin (HT) is an aglycone metabolite of HD with high bioavailability. Through the docking simulation, HD and HT have shown their potential to bind to two cellular proteins: transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2), which are required for the cellular entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results further found that HT and HD suppressed the infection of VeroE6 cells using lentiviral-based pseudo-particles with wild types and variants of SARS-CoV-2 with spike (S) proteins, by blocking the interaction between the S protein and cellular receptor ACE2 and reducing ACE2 and TMPRSS2 expression. In summary, hesperidin is a potential TMPRSS2 inhibitor for the reduction of the SARS-CoV-2 infection.
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Ou, Tianling, Huihui Mou, Lizhou Zhang, Amrita Ojha, Hyeryun Choe, and Michael Farzan. "Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2." PLOS Pathogens 17, no. 1 (January 19, 2021): e1009212. http://dx.doi.org/10.1371/journal.ppat.1009212.
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Hydroxychloroquine, used to treat malaria and some autoimmune disorders, potently inhibits viral infection of SARS coronavirus (SARS-CoV-1) and SARS-CoV-2 in cell-culture studies. However, human clinical trials of hydroxychloroquine failed to establish its usefulness as treatment for COVID-19. This compound is known to interfere with endosomal acidification necessary to the proteolytic activity of cathepsins. Following receptor binding and endocytosis, cathepsin L can cleave the SARS-CoV-1 and SARS-CoV-2 spike (S) proteins, thereby activating membrane fusion for cell entry. The plasma membrane-associated protease TMPRSS2 can similarly cleave these S proteins and activate viral entry at the cell surface. Here we show that the SARS-CoV-2 entry process is more dependent than that of SARS-CoV-1 on TMPRSS2 expression. This difference can be reversed when the furin-cleavage site of the SARS-CoV-2 S protein is ablated or when it is introduced into the SARS-CoV-1 S protein. We also show that hydroxychloroquine efficiently blocks viral entry mediated by cathepsin L, but not by TMPRSS2, and that a combination of hydroxychloroquine and a clinically-tested TMPRSS2 inhibitor prevents SARS-CoV-2 infection more potently than either drug alone. These studies identify functional differences between SARS-CoV-1 and -2 entry processes, and provide a mechanistic explanation for the limited in vivo utility of hydroxychloroquine as a treatment for COVID-19.
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Papa, Guido, Donna L. Mallery, Anna Albecka, Lawrence G. Welch, Jérôme Cattin-Ortolá, Jakub Luptak, David Paul, et al. "Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion." PLOS Pathogens 17, no. 1 (January 25, 2021): e1009246. http://dx.doi.org/10.1371/journal.ppat.1009246.
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Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infects cells by binding to the host cell receptor ACE2 and undergoing virus-host membrane fusion. Fusion is triggered by the protease TMPRSS2, which processes the viral Spike (S) protein to reveal the fusion peptide. SARS-CoV-2 has evolved a multibasic site at the S1-S2 boundary, which is thought to be cleaved by furin in order to prime S protein for TMPRSS2 processing. Here we show that CRISPR-Cas9 knockout of furin reduces, but does not prevent, the production of infectious SARS-CoV-2 virus. Comparing S processing in furin knockout cells to multibasic site mutants reveals that while loss of furin substantially reduces S1-S2 cleavage it does not prevent it. SARS-CoV-2 S protein also mediates cell-cell fusion, potentially allowing virus to spread virion-independently. We show that loss of furin in either donor or acceptor cells reduces, but does not prevent, TMPRSS2-dependent cell-cell fusion, unlike mutation of the multibasic site that completely prevents syncytia formation. Our results show that while furin promotes both SARS-CoV-2 infectivity and cell-cell spread it is not essential, suggesting furin inhibitors may reduce but not abolish viral spread.
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Ravaioli, Sara, Michela Tebaldi, Eugenio Fonzi, Davide Angeli, Massimiliano Mazza, Fabio Nicolini, Alessandro Lucchesi, et al. "ACE2 and TMPRSS2 Potential Involvement in Genetic Susceptibility to SARS-COV-2 in Cancer Patients." Cell Transplantation 29 (January 1, 2020): 096368972096874. http://dx.doi.org/10.1177/0963689720968749.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. One open question is whether genetics could influence the severity of symptoms. Considering the limited data on cancer patients, we analyzed public data repositories limited to investigate angiotensin-converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2) expressions and genetic variants to identify the basis of individual susceptibility to SARS-CoV-2. Gene expression and variant data were retrieved from Tissue Cancer Genome Atlas, Genotype-Tissue Expression, and gnomAD. Differences in gene expression were tested with Mann-Whitney U-test. Allele frequencies of germline variants were explored in different ethnicities, with a special focus on ACE2 variants located in the binding site to SARS-CoV-2 spike protein. The analysis of ACE2 and TMPRSS2 expressions in healthy tissues showed a higher expression in the age class 20 to 59 years (false discovery rate [FDR] < 0.0001) regardless of gender. ACE2 and TMPRSS2 were more expressed in tumors from males than females (both FDR < 0.0001) and, opposite to the regulation in tissues from healthy individuals, more expressed in elderly patients (FDR = 0.005; FDR < 0.0001, respectively). ACE2 and TMPRSS2 expressions were higher in cancers of elderly patients compared with healthy individuals (FDR < 0.0001). Variants were present at low frequency (range 0% to 3%) and among those with the highest frequency, the variant S19P belongs to the SARS-CoV-2 spike protein binding site and it was exclusively present in Africans with a frequency of 0.2%. The mechanisms of ACE2 and TMPRSS2 regulation could be targeted for preventive and therapeutic purposes in the whole population and especially in cancer patients. Further studies are needed to show a direct correlation of ACE2 and TMPRSS2 expressions in cancer patients and the incidence of COVID-19.
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Darapaneni, V., and A. Jaldani. "Membrane protein of SARS-CoV-2 plays a pivotal role in the availability of active testosterone through its interaction with AKR1C2 enzyme leading to the upregulation of TMPRSS2 protease expression." Microbiology Independent Research Journal (MIR Journal) 8, no. 1 (March 18, 2021): 38–40. http://dx.doi.org/10.18527/2500-2236-2021-8-1-38-40.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease (COVID-19) and ongoing pandemic that has devastated humankind. During the COVID-19 pandemic, it was noticed that the mortality rate in men is higher than that in women. The membrane (M) protein of SARS-CoV-2 plays a pivotal role in the viral life cycle regulating intracellular trafficking and processing of spike (S) protein. In infected individuals, M protein inhibits the conversion of active testosterone to its inactive form through its interaction with Aldo-keto reductase family 1 member C2 (AKR1C2) protein. This leads to the high availability of active testosterone and boosts the formation of its complex with an androgen receptor that in turn promotes the transcription of the transmembrane protease serine 2 (TMPRSS2) gene. TMPRSS2 is known to play a pivotal role in the priming of S protein that is necessary for the SARS-CoV-2 entry into the host cell. Therefore, the interaction of the M protein of SARSCoV-2 with AKR1C2 eventually leads to the upregulation of the transcription of the TMPRSS2 gene that results in an enhanced viral infection and in turn higher mortality in men. The interaction of M protein with AKR1C2 could be a possible target for SARSCoV-2 antiviral drug design.
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Ahmad Mulyadi Lai, Henkie Isahwan, Shih-Jie Chou, Yueh Chien, Ping-Hsing Tsai, Chian-Shiu Chien, Chih-Chien Hsu, Ying-Chun Jheng, et al. "Expression of Endogenous Angiotensin-Converting Enzyme 2 in Human Induced Pluripotent Stem Cell-Derived Retinal Organoids." International Journal of Molecular Sciences 22, no. 3 (January 28, 2021): 1320. http://dx.doi.org/10.3390/ijms22031320.
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Angiotensin-converting enzyme 2 (ACE2) was identified as the main host cell receptor for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its subsequent infection. In some coronavirus disease 2019 (COVID-19) patients, it has been reported that the nervous tissues and the eyes were also affected. However, evidence supporting that the retina is a target tissue for SARS-CoV-2 infection is still lacking. This present study aimed to investigate whether ACE2 expression plays a role in human retinal neurons during SARS-CoV-2 infection. Human induced pluripotent stem cell (hiPSC)-derived retinal organoids and monolayer cultures derived from dissociated retinal organoids were generated. To validate the potential entry of SARS-CoV-2 infection in the retina, we showed that hiPSC-derived retinal organoids and monolayer cultures endogenously express ACE2 and transmembrane serine protease 2 (TMPRSS2) on the mRNA level. Immunofluorescence staining confirmed the protein expression of ACE2 and TMPRSS2 in retinal organoids and monolayer cultures. Furthermore, using the SARS-CoV-2 pseudovirus spike protein with GFP expression system, we found that retinal organoids and monolayer cultures can potentially be infected by the SARS-CoV-2 pseudovirus. Collectively, our findings highlighted the potential of iPSC-derived retinal organoids as the models for ACE2 receptor-based SARS-CoV-2 infection.
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Xu, Chuan, Annie Wang, Ke Geng, William Honnen, Xuening Wang, Natalie Bruiners, Sukhwinder Singh, et al. "Human Immunodeficiency Viruses Pseudotyped with SARS-CoV-2 Spike Proteins Infect a Broad Spectrum of Human Cell Lines through Multiple Entry Mechanisms." Viruses 13, no. 6 (May 21, 2021): 953. http://dx.doi.org/10.3390/v13060953.
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Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2), the causative agent of coronavirus disease 19 (COVID-19), enters cells through attachment to the human angiotensin converting enzyme 2 (hACE2) via the receptor-binding domain (RBD) in the surface/spike (S) protein. Several pseudotyped viruses expressing SARS-CoV-2 S proteins are available, but many of these can only infect hACE2-overexpressing cell lines. Here, we report the use of a simple, two-plasmid, pseudotyped virus system comprising a SARS-CoV-2 spike-expressing plasmid and an HIV vector with or without vpr to investigate the SARS-CoV-2 entry event in various cell lines. When an HIV vector without vpr was used, pseudotyped SARS-CoV-2 viruses produced in the presence of fetal bovine serum (FBS) were able to infect only engineered hACE2-overexpressing cell lines, whereas viruses produced under serum-free conditions were able to infect a broader range of cells, including cells without hACE2 overexpression. When an HIV vector containing vpr was used, pseudotyped viruses were able to infect a broad spectrum of cell types regardless of whether viruses were produced in the presence or absence of FBS. Infection sensitivities of various cell types did not correlate with mRNA abundance of hACE2, TMPRSS2, or TMPRSS4. Pseudotyped SARS-CoV-2 viruses and replication-competent SARS-CoV-2 virus were equally sensitive to neutralization by an anti-spike RBD antibody in cells with high abundance of hACE2. However, the anti-spike RBD antibody did not block pseudotyped viral entry into cell lines with low abundance of hACE2. We further found that CD147 was involved in viral entry in A549 cells with low abundance of hACE2. Thus, our assay is useful for drug and antibody screening as well as for investigating cellular receptors, including hACE2, CD147, and tyrosine-protein kinase receptor UFO (AXL), for the SARS-CoV-2 entry event in various cell lines.
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Choi, Yoonjung, Bonggun Shin, Keunsoo Kang, Sungsoo Park, and Bo Ram Beck. "Target-Centered Drug Repurposing Predictions of Human Angiotensin-Converting Enzyme 2 (ACE2) and Transmembrane Protease Serine Subtype 2 (TMPRSS2) Interacting Approved Drugs for Coronavirus Disease 2019 (COVID-19) Treatment through a Drug-Target Interaction Deep Learning Model." Viruses 12, no. 11 (November 18, 2020): 1325. http://dx.doi.org/10.3390/v12111325.
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Previously, our group predicted commercially available Food and Drug Administration (FDA) approved drugs that can inhibit each step of the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using a deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI). Unfortunately, additional clinically significant treatment options since the approval of remdesivir are scarce. To overcome the current coronavirus disease 2019 (COVID-19) more efficiently, a treatment strategy that controls not only SARS-CoV-2 replication but also the host entry step should be considered. In this study, we used MT-DTI to predict FDA approved drugs that may have strong affinities for the angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane protease serine 2 (TMPRSS2) which are essential for viral entry to the host cell. Of the 460 drugs with Kd of less than 100 nM for the ACE2 receptor, 17 drugs overlapped with drugs that inhibit the interaction of ACE2 and SARS-CoV-2 spike reported in the NCATS OpenData portal. Among them, enalaprilat, an ACE inhibitor, showed a Kd value of 1.5 nM against the ACE2. Furthermore, three of the top 30 drugs with strong affinity prediction for the TMPRSS2 are anti-hepatitis C virus (HCV) drugs, including ombitasvir, daclatasvir, and paritaprevir. Notably, of the top 30 drugs, AT1R blocker eprosartan and neuropsychiatric drug lisuride showed similar gene expression profiles to potential TMPRSS2 inhibitors. Collectively, we suggest that drugs predicted to have strong inhibitory potencies to ACE2 and TMPRSS2 through the DTI model should be considered as potential drug repurposing candidates for COVID-19.
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Liu, Hanning, Shujie Gai, Xiaoyi Wang, Juntong Zeng, Cheng Sun, Yan Zhao, and Zhe Zheng. "Single-cell analysis of SARS-CoV-2 receptor ACE2 and spike protein priming expression of proteases in the human heart." Cardiovascular Research 116, no. 10 (July 8, 2020): 1733–41. http://dx.doi.org/10.1093/cvr/cvaa191.
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Abstract Aims Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly binds to ACE2 (angiotensin-converting enzyme 2) to facilitate cellular entry. Compared with the lung or respiratory tract, the human heart exhibits greater ACE2 expression. However, little substantial damage was found in the heart tissue, and no viral particles were observed in the cardiac myocytes. This study aims to analyse ACE2 and SARS-CoV-2 spike (S) protein proteases at the single-cell level, to explore the cardiac involvement in COVID-19 and improve our understanding of the potential cardiovascular implications of COVID-19. Methods and Results With meta-analysis, the prevalence of cardiac injury in COVID-19 patients varies from 2% [95% confidence interval (CI) 0–5%, I2 = 0%] in non-ICU patients to 59% (95% CI 48–71%, I2 = 85%) in non-survivors. With public single-cell sequence data analysis, ACE2 expression in the adult human heart is higher than that in the lung (adjusted P < 0.0001). Inversely, the most important S protein cleavage protease TMPRSS2 (transmembrane protease serine protease-2) in the heart exhibits an extremely lower expression than that in the lung (adjusted P < 0.0001), which may restrict entry of SARS-CoV-2 into cardiac cells. Furthermore, we discovered that other S protein proteases, CTSL (cathepsin L) and FURIN (furin, paired basic amino acid cleaving enzyme), were expressed in the adult heart at a similar level to that in the lung, which may compensate for TMPRSS2, mediating cardiac involvement in COVID-19. Conclusion Compared with the lung, ACE2 is relatively more highly expressed in the human heart, while the key S protein priming protease, TMPRSS2, is rarely expressed. The low percentage of ACE2+/TMPRSS2+ cells reduced heart vulnerability to SARS-CoV-2 to some degree. CTSL and FURIN may compensate for S protein priming to mediate SARS-CoV-2 infection of the heart.
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Sasaki, Michihito, Kentaro Uemura, Akihiko Sato, Shinsuke Toba, Takao Sanaki, Katsumi Maenaka, William W. Hall, Yasuko Orba, and Hirofumi Sawa. "SARS-CoV-2 variants with mutations at the S1/S2 cleavage site are generated in vitro during propagation in TMPRSS2-deficient cells." PLOS Pathogens 17, no. 1 (January 21, 2021): e1009233. http://dx.doi.org/10.1371/journal.ppat.1009233.
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The spike (S) protein of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) binds to a host cell receptor which facilitates viral entry. A polybasic motif detected at the cleavage site of the S protein has been shown to broaden the cell tropism and transmissibility of the virus. Here we examine the properties of SARS-CoV-2 variants with mutations at the S protein cleavage site that undergo inefficient proteolytic cleavage. Virus variants with S gene mutations generated smaller plaques and exhibited a more limited range of cell tropism compared to the wild-type strain. These alterations were shown to result from their inability to utilize the entry pathway involving direct fusion mediated by the host type II transmembrane serine protease, TMPRSS2. Notably, viruses with S gene mutations emerged rapidly and became the dominant SARS-CoV-2 variants in TMPRSS2-deficient cells including Vero cells. Our study demonstrated that the S protein polybasic cleavage motif is a critical factor underlying SARS-CoV-2 entry and cell tropism. As such, researchers should be alert to the possibility of de novo S gene mutations emerging in tissue-culture propagated virus strains.
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Gupta, Ishita, Balsam Rizeq, Eyad Elkord, Semir Vranic, and Ala-Eddin Al Moustafa. "SARS-CoV-2 Infection and Lung Cancer: Potential Therapeutic Modalities." Cancers 12, no. 8 (August 5, 2020): 2186. http://dx.doi.org/10.3390/cancers12082186.
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Human coronaviruses, especially SARS-CoV-2, are emerging pandemic infectious diseases with high morbidity and mortality in certain group of patients. In general, SARS-CoV-2 causes symptoms ranging from the common cold to severe conditions accompanied by lung injury, acute respiratory distress syndrome in addition to other organs’ destruction. The main impact upon SARS-CoV-2 infection is damage to alveolar and acute respiratory failure. Thus, lung cancer patients are identified as a particularly high-risk group for SARS-CoV-2 infection and its complications. On the other hand, it has been reported that SARS-CoV-2 spike (S) protein binds to angiotensin-converting enzyme 2 (ACE-2), that promotes cellular entry of this virus in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2). Today, there are no vaccines and/or effective drugs against the SARS-CoV-2 coronavirus. Thus, manipulation of key entry genes of this virus especially in lung cancer patients could be one of the best approaches to manage SARS-CoV-2 infection in this group of patients. We herein provide a comprehensive and up-to-date overview of the role of ACE-2 and TMPRSS2 genes, as key entry elements as well as therapeutic targets for SARS-CoV-2 infection, which can help to better understand the applications and capacities of various remedial approaches for infected individuals, especially those with lung cancer.
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Aleksova, Aneta, Giulia Gagno, Gianfranco Sinagra, Antonio Paolo Beltrami, Milijana Janjusevic, Giuseppe Ippolito, Alimuddin Zumla, Alessandra Lucia Fluca, and Federico Ferro. "Effects of SARS-CoV-2 on Cardiovascular System: The Dual Role of Angiotensin-Converting Enzyme 2 (ACE2) as the Virus Receptor and Homeostasis Regulator-Review." International Journal of Molecular Sciences 22, no. 9 (April 26, 2021): 4526. http://dx.doi.org/10.3390/ijms22094526.
Full textAbstract:
Angiotensin-converting enzyme 2 (ACE2) is the entry receptor for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of Coronavirus Disease-2019 (COVID-19) in humans. ACE-2 is a type I transmembrane metallocarboxypeptidase expressed in vascular endothelial cells, alveolar type 2 lung epithelial cells, renal tubular epithelium, Leydig cells in testes and gastrointestinal tract. ACE2 mediates the interaction between host cells and SARS-CoV-2 spike (S) protein. However, ACE2 is not only a SARS-CoV-2 receptor, but it has also an important homeostatic function regulating renin-angiotensin system (RAS), which is pivotal for both the cardiovascular and immune systems. Therefore, ACE2 is the key link between SARS-CoV-2 infection, cardiovascular diseases (CVDs) and immune response. Susceptibility to SARS-CoV-2 seems to be tightly associated with ACE2 availability, which in turn is determined by genetics, age, gender and comorbidities. Severe COVID-19 is due to an uncontrolled and excessive immune response, which leads to acute respiratory distress syndrome (ARDS) and multi-organ failure. In spite of a lower ACE2 expression on cells surface, patients with CVDs have a higher COVID-19 mortality rate, which is likely driven by the imbalance between ADAM metallopeptidase domain 17 (ADAM17) protein (which is required for cleavage of ACE-2 ectodomain resulting in increased ACE2 shedding), and TMPRSS2 (which is required for spike glycoprotein priming). To date, ACE inhibitors and Angiotensin II Receptor Blockers (ARBs) treatment interruption in patients with chronic comorbidities appears unjustified. The rollout of COVID-19 vaccines provides opportunities to study the effects of different COVID-19 vaccines on ACE2 in patients on treatment with ACEi/ARB.
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Ezechukwu, Henry C., Cornelius A. Diya, Ifunanya J. Egoh, Mayowa J. Abiodun, John-Ugwuanya A. Grace, God’spower R. Okoh, Kayode T. Adu, and Oyelola A. Adegboye. "Lung microbiota dysbiosis and the implications of SARS-CoV-2 infection in pregnancy." Therapeutic Advances in Infectious Disease 8 (January 2021): 204993612110324. http://dx.doi.org/10.1177/20499361211032453.
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There are a great number of beneficial commensal microorganisms constitutively colonizing the mucosal lining of the lungs. Alterations in the microbiota profile have been associated with several respiratory diseases such as pneumonia and allergies. Lung microbiota dysbiosis might play an important role in the pathogenic mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as elicit other opportunistic infections associated with coronavirus disease 2019 (COVID-19). With its increasing prevalence and morbidity, SARS-CoV-2 infection in pregnant mothers is inevitable. Recent evidence shows that angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) act as an entry receptor and viral spike priming protein, respectively, for SARS-CoV-2 infection. These receptor proteins are highly expressed in the maternal-fetal interface, including the placental trophoblast, suggesting the possibility of maternal–fetal transmission. In this review, we discuss the role of lung microbiota dysbiosis in respiratory diseases, with an emphasis on COVID-19 and the possible implications of SARS-CoV-2 infection on pregnancy outcome and neonatal health.
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HUYNH, Mai T. N., Phuc H. T. NGUYEN, Hieu H. C. PHAN, Nghia T. H. PHAN, Kong H. LE, Nhu T. H. TRUONG, Khanh LE, et al. "A review of COVID-19: Molecular basis, diagnosis, therapeutics and prevention." Science and Technology Development Journal - Natural Sciences 4, no. 3 (July 1, 2020): First. http://dx.doi.org/10.32508/stdjns.v4i3.907.
Full textAbstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the confirmed viral pathogen of COVID-19, a pandemic originated from Wuhan, China at the end of 2019. Since then, SARS-CoV-2 has rapidly spread across the globe with over 8 million confirmed cases and more than 430.000 deaths worldwide as of mid-June 2020. Similar to other strains of coronavirus, the envelope of SARS-CoV-2 comprises of three structural proteins: S protein (spike), E protein (envelope) and M glycoprotein (membrane). SARS-CoV-2 capsids are spherical or pleomorphic. Each capsid contains a positive-sense single-stranded RNA (+ssRNA-Class IV-Baltimore) associated with nucleoprotein N. The viral RNA genome is approximately 30 kb in length and contains 14 open reading frames (ORFs). The binding affinity of the viral S protein to the ACE2 (angiotensin-converting enzyme 2) receptor facilitates the attachment of SARS-CoV-2 to human epithelial cells. Upon binding, SARS-CoV-2 spike protein is cleaved and activated by TMPRSS2 (transmembrane protease, serine 2) or by cathepsin L at the cleavage site S2', and also by furin at the cleavage site S1/S2. The furin cleavage motif RR_R is a notable feature, firstly found in SARS-CoV-2 S protein, which may increase virus transmission rate. This feature and many others might result from several evolution events in SARS-CoV-2 genome. These events could occur when coronaviruses, including SARS-CoV-2, spread from one host to another. They can be causative to high virulence and transmission rate of future coronavirus strains, which may require the development of newer vaccine generations. To understand of SARS-CoV-2’s structure, infection mechanism, diagnosis, treatment, and vaccine development strategies, a review of current literature is of highly importance to disease control in Vietnam.
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Meyer, Daniela, Frank Sielaff, Maya Hammami, Eva Böttcher-Friebertshäuser, Wolfgang Garten, and Torsten Steinmetzer. "Identification of the first synthetic inhibitors of the type II transmembrane serine protease TMPRSS2 suitable for inhibition of influenza virus activation." Biochemical Journal 452, no. 2 (May 10, 2013): 331–43. http://dx.doi.org/10.1042/bj20130101.
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TMPRSS2 (transmembrane serine proteinase 2) is a multidomain type II transmembrane serine protease that cleaves the surface glycoprotein HA (haemagglutinin) of influenza viruses with a monobasic cleavage site, which is a prerequisite for virus fusion and propagation. Furthermore, it activates the fusion protein F of the human metapneumovirus and the spike protein S of the SARS-CoV (severe acute respiratory syndrome coronavirus). Increased TMPRSS2 expression was also described in several tumour entities. Therefore TMPRSS2 emerged as a potential target for drug design. The catalytic domain of TMPRSS2 was expressed in Escherichia coli and used for an inhibitor screen with previously synthesized inhibitors of various trypsin-like serine proteases. Two inhibitor types were identified which inhibit TMPRSS2 in the nanomolar range. The first series comprises substrate analogue inhibitors containing a 4-amidinobenzylamide moiety at the P1 position, whereby some of these analogues possess inhibition constants of approximately 20 nM. An improved potency was found for a second type derived from sulfonylated 3-amindinophenylalanylamide derivatives. The most potent derivative of this series inhibits TMPRSS2 with a Ki value of 0.9 nM and showed an efficient blockage of influenza virus propagation in human airway epithelial cells. On the basis of the inhibitor studies, a series of new fluorogenic substrates containing a D-arginine residue at the P3 position was synthesized, some of them were efficiently cleaved by TMPRSS2.
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McGill, Andrew R., Roukiah Kahlil, Rinku Dutta, Ryan Green, Mark Howell, Subhra Mohapatra, and Shyam S. Mohapatra. "SARS–CoV-2 Immuno-Pathogenesis and Potential for Diverse Vaccines and Therapies: Opportunities and Challenges." Infectious Disease Reports 13, no. 1 (February 4, 2021): 102–25. http://dx.doi.org/10.3390/idr13010013.
Full textAbstract:
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel coronavirus that emerged from Wuhan, China in late 2019 causing coronavirus disease-19 (COVID-19). SARS-CoV-2 infection begins by attaching to angiotensin-converting enzyme 2 receptor (ACE2) via the spike glycoprotein, followed by cleavage by TMPRSS2, revealing the viral fusion domain. Other presumptive receptors for SARS-CoV-2 attachment include CD147, neuropilin-1 (NRP1), and Myeloid C-lectin like receptor (CLR), each of which might play a role in the systemic viral spread. The pathology of SARS-CoV-2 infection ranges from asymptomatic to severe acute respiratory distress syndrome, often displaying a cytokine storm syndrome, which can be life-threatening. Despite progress made, the detailed mechanisms underlying SARS-CoV-2 interaction with the host immune system remain unclear and are an area of very active research. The process’s key players include viral non-structural proteins and open reading frame products, which have been implicated in immune antagonism. The dysregulation of the innate immune system results in reduced adaptive immune responses characterized by rapidly diminishing antibody titers. Several treatment options for COVID-19 are emerging, with immunotherapies, peptide therapies, and nucleic acid vaccines showing promise. This review discusses the advances in the immunopathology of SARS-CoV-2, vaccines and therapies under investigation to counter the effects of this virus, as well as viral variants.
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Yadav, Rohitash, Jitendra Kumar Chaudhary, Neeraj Jain, Pankaj Kumar Chaudhary, Supriya Khanra, Puneet Dhamija, Ambika Sharma, Ashish Kumar, and Shailendra Handu. "Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19." Cells 10, no. 4 (April 6, 2021): 821. http://dx.doi.org/10.3390/cells10040821.
Full textAbstract:
Coronavirus belongs to the family of Coronaviridae, comprising single-stranded, positive-sense RNA genome (+ ssRNA) of around 26 to 32 kilobases, and has been known to cause infection to a myriad of mammalian hosts, such as humans, cats, bats, civets, dogs, and camels with varied consequences in terms of death and debilitation. Strikingly, novel coronavirus (2019-nCoV), later renamed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and found to be the causative agent of coronavirus disease-19 (COVID-19), shows 88% of sequence identity with bat-SL-CoVZC45 and bat-SL-CoVZXC21, 79% with SARS-CoV and 50% with MERS-CoV, respectively. Despite key amino acid residual variability, there is an incredible structural similarity between the receptor binding domain (RBD) of spike protein (S) of SARS-CoV-2 and SARS-CoV. During infection, spike protein of SARS-CoV-2 compared to SARS-CoV displays 10–20 times greater affinity for its cognate host cell receptor, angiotensin-converting enzyme 2 (ACE2), leading proteolytic cleavage of S protein by transmembrane protease serine 2 (TMPRSS2). Following cellular entry, the ORF-1a and ORF-1ab, located downstream to 5′ end of + ssRNA genome, undergo translation, thereby forming two large polyproteins, pp1a and pp1ab. These polyproteins, following protease-induced cleavage and molecular assembly, form functional viral RNA polymerase, also referred to as replicase. Thereafter, uninterrupted orchestrated replication-transcription molecular events lead to the synthesis of multiple nested sets of subgenomic mRNAs (sgRNAs), which are finally translated to several structural and accessory proteins participating in structure formation and various molecular functions of virus, respectively. These multiple structural proteins assemble and encapsulate genomic RNA (gRNA), resulting in numerous viral progenies, which eventually exit the host cell, and spread infection to rest of the body. In this review, we primarily focus on genomic organization, structural and non-structural protein components, and potential prospective molecular targets for development of therapeutic drugs, convalescent plasm therapy, and a myriad of potential vaccines to tackle SARS-CoV-2 infection.
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Shabani, Fatemeh, Alireza Farasat, Peyman Namdar, and Nematollah Gheibi. "Investigating the Mechanism of Action of SARS-CoV-2 Virus for Drug Designing: A Review." Journal of Qazvin University of Medical Sciences 24, no. 2 (June 30, 2020): 158–77. http://dx.doi.org/10.32598/jqums.24.2.708.3.
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Coronavirus Disease 2019 (COVID-19) is a viral pneumonia emerged in December 2019 in Wuhan, China. Its cause is a new virus from the coronavirus family scientifically named Coronavirus Acute Respiratory Syndrome 2 (SARS-CoV-2). In this review study, articles published in English until March 23, 2020 on new coronavirus infection were reviewed. These articles are obtained by searching in PubMed, Scopus and Google scholar databases using keywords "SARS-CoV-2", "COVID-19" and "Coronavirus". The latest COVID-19 statistics and information were extracted from the websites of World Health Organization and the Centers for Disease Control and Prevention. we investigated the effect of different compounds on the key macromolecules in promoting SARS-COV-2 infection using computational methods and bioinformatics analysis that can be considered as the best targets for designing inhibitory drugs. The most important macromolecules were Angiotensin Converting Enzyme 2 (ACE2) and Transmembrane Protease Serine 2 (TMPRSS2) receptors of the host cell surface and the structural and non-structural proteins of the virus. The most important structural protein was Spike, playing an important role in binding the virus to the ACE2 receptor of the host cell and the entery of the virus genome into it, while the key non-structural proteins were 3-Chymotrypsin-like protease (3CLpro), RNA-dependent RNA polymerase (RdRp), Papain-like cysteine proteinase (PLpro), and non-structural protein 13 (nsp13) helicase which are involved in viral genome replication and the virus’ release from the host cell.
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Chen, Ting-Fu, Yu-Chuan Chang, Yi Hsiao, Ko-Han Lee, Yu-Chun Hsiao, Yu-Hsiang Lin, Yi-Chin Ethan Tu, Hsuan-Cheng Huang, Chien-Yu Chen, and Hsueh-Fen Juan. "DockCoV2: a drug database against SARS-CoV-2." Nucleic Acids Research 49, no. D1 (October 9, 2020): D1152—D1159. http://dx.doi.org/10.1093/nar/gkaa861.
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Abstract The current state of the COVID-19 pandemic is a global health crisis. To fight the novel coronavirus, one of the best-known ways is to block enzymes essential for virus replication. Currently, we know that the SARS-CoV-2 virus encodes about 29 proteins such as spike protein, 3C-like protease (3CLpro), RNA-dependent RNA polymerase (RdRp), Papain-like protease (PLpro), and nucleocapsid (N) protein. SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) for viral entry and transmembrane serine protease family member II (TMPRSS2) for spike protein priming. Thus in order to speed up the discovery of potential drugs, we develop DockCoV2, a drug database for SARS-CoV-2. DockCoV2 focuses on predicting the binding affinity of FDA-approved and Taiwan National Health Insurance (NHI) drugs with the seven proteins mentioned above. This database contains a total of 3,109 drugs. DockCoV2 is easy to use and search against, is well cross-linked to external databases, and provides the state-of-the-art prediction results in one site. Users can download their drug-protein docking data of interest and examine additional drug-related information on DockCoV2. Furthermore, DockCoV2 provides experimental information to help users understand which drugs have already been reported to be effective against MERS or SARS-CoV. DockCoV2 is available at https://covirus.cc/drugs/.
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Huang, Szu-Wei, and Sheng-Fan Wang. "SARS-CoV-2 Entry Related Viral and Host Genetic Variations: Implications on COVID-19 Severity, Immune Escape, and Infectivity." International Journal of Molecular Sciences 22, no. 6 (March 17, 2021): 3060. http://dx.doi.org/10.3390/ijms22063060.
Full textAbstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved to display particular patterns of genetic diversity in the genome across geographical regions. These variations in the virus and genetic variation in human populations can determine virus transmissibility and coronavirus disease 2019 (COVID-19) severity. Genetic variations and immune differences in human populations could be the driving forces in viral evolution. Recently emerged SARS-CoV-2 variants show several mutations at the receptor binding domain in the spike (S) glycoprotein and contribute to immune escape and enhanced binding with angiotensin 1-converting enzyme 2 (ACE2). Since ACE2 and transmembrane protease serine 2 (TMPRSS2) play important roles in SARS-CoV-2 entry into the cell, genetic variation in these host entry-related proteins may be a driving force for positive selection in the SARS-CoV-2 S glycoprotein. Dendritic or liver/lymph cell-specific intercellular adhesion molecule (ICAM)-3-grabbing non-integrin is also known to play vital roles in several pathogens. Genetic variations of these host proteins may affect the susceptibility to SARS-CoV-2. This review summarizes the latest research to describe the impacts of genetic variation in the viral S glycoprotein and critical host proteins and aims to provide better insights for understanding transmission and pathogenesis and more broadly for developing vaccine/antiviral drugs and precision medicine strategies, especially for high risk populations with genetic risk variants.
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Davidson, Anne M., Jan Wysocki, and Daniel Batlle. "Interaction of SARS-CoV-2 and Other Coronavirus With ACE (Angiotensin-Converting Enzyme)-2 as Their Main Receptor." Hypertension 76, no. 5 (November 2020): 1339–49. http://dx.doi.org/10.1161/hypertensionaha.120.15256.
Full textAbstract:
Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 originated from Wuhan, China, in December 2019 and rapidly spread to other areas worldwide. Since then, coronavirus disease 2019 (COVID-19) has reached pandemic proportions with >570 000 deaths globally by mid-July 2020. The magnitude of the outbreak and the potentially severe clinical course of COVID-19 has led to a burst of scientific research on this novel coronavirus and its host receptor ACE (angiotensin-converting enzyme)-2. ACE2 is a homolog of the ACE that acts on several substrates in the renin-Ang (angiotensin) system. With unprecedented speed, scientific research has solved the structure of SARS-CoV-2 and imaged its binding with the ACE2 receptor. In SARS-CoV-2 infection, the viral S (spike) protein receptor-binding domain binds to ACE2 to enter the host cell. ACE2 expression in the lungs is relatively low, but it is present in type II pneumocytes—a cell type also endowed with TMPRSS2 (transmembrane protease serine 2). This protease is critical for priming the SARS-CoV-2 S protein to complex with ACE2 and enter the cells. Herein, we review the current understanding of the interaction of SARS-CoV-2 with ACE2 as it has rapidly unfolded over the last months. While it should not be assumed that we have a complete picture of SARS-CoV-2 mechanism of infection and its interaction with ACE2, much has been learned with clear therapeutic implications. Potential therapies aimed at intercepting SARS-CoV-2 from reaching the full-length membrane-bound ACE2 receptor using soluble ACE2 protein and other potential approaches are briefly discussed as well.
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Vianello, Annamaria, Serena Del Turco, Serena Babboni, Beatrice Silvestrini, Rosetta Ragusa, Chiara Caselli, Luca Melani, Luca Fanucci, and Giuseppina Basta. "The Fight against COVID-19 on the Multi-Protease Front and Surroundings: Could an Early Therapeutic Approach with Repositioning Drugs Prevent the Disease Severity?" Biomedicines 9, no. 7 (June 23, 2021): 710. http://dx.doi.org/10.3390/biomedicines9070710.
Full textAbstract:
The interaction between the membrane spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the transmembrane angiotensin-converting enzyme 2 (ACE2) receptor of the human epithelial host cell is the first step of infection, which has a critical role for viral pathogenesis of the current coronavirus disease-2019 (COVID-19) pandemic. Following the binding between S1 subunit and ACE2 receptor, different serine proteases, including TMPRSS2 and furin, trigger and participate in the fusion of the viral envelope with the host cell membrane. On the basis of the high virulence and pathogenicity of SARS-CoV-2, other receptors have been found involved for viral binding and invasiveness of host cells. This review comprehensively discusses the mechanisms underlying the binding of SARS-CoV2 to ACE2 and putative alternative receptors, and the role of potential co-receptors and proteases in the early stages of SARS-CoV-2 infection. Given the short therapeutic time window within which to act to avoid the devastating evolution of the disease, we focused on potential therapeutic treatments—selected mainly among repurposing drugs—able to counteract the invasive front of proteases and mild inflammatory conditions, in order to prevent severe infection. Using existing approved drugs has the advantage of rapidly proceeding to clinical trials, low cost and, consequently, immediate and worldwide availability.
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Bellamine, Aouatef, Tram N. Q. Pham, Jaspreet Jain, Jacob Wilson, Kazim Sahin, Frederic Dallaire, Nabil G. Seidah, Shane Durkee, Katarina Radošević, and Éric A. Cohen. "L-Carnitine Tartrate Downregulates the ACE2 Receptor and Limits SARS-CoV-2 Infection." Nutrients 13, no. 4 (April 14, 2021): 1297. http://dx.doi.org/10.3390/nu13041297.
Full textAbstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for one of the worst pandemics in modern history. Several prevention and treatment strategies have been designed and evaluated in recent months either through the repurposing of existing treatments or the development of new drugs and vaccines. In this study, we show that L-carnitine tartrate supplementation in humans and rodents led to significant decreases of key host dependency factors, notably angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), and Furin, which are responsible for viral attachment, viral spike S-protein cleavage, and priming for viral fusion and entry. Interestingly, pre-treatment of Calu-3, human lung epithelial cells, with L-carnitine tartrate led to a significant and dose-dependent inhibition of the infection by SARS-CoV-2. Infection inhibition coincided with a significant decrease in ACE2 mRNA expression levels. These data suggest that L-carnitine tartrate should be tested with appropriate trials in humans for the possibility to limit SARS-CoV-2 infection.
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Chueh, Ti-I., Cai-Mei Zheng, Yi-Chou Hou, and Kuo-Cheng Lu. "Novel Evidence of Acute Kidney Injury in COVID-19." Journal of Clinical Medicine 9, no. 11 (November 3, 2020): 3547. http://dx.doi.org/10.3390/jcm9113547.
Full textAbstract:
The coronavirus 2019 (COVID-19) pandemic has caused a huge impact on health and economic issues. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes cellular damage by entry mediated by the angiotensin-converting enzyme 2 of the host cells and its conjugation with spike proteins of SARS-CoV-2. Beyond airway infection and acute respiratory distress syndrome, acute kidney injury is common in SARS-CoV-2-associated infection, and acute kidney injury (AKI) is predictive to multiorgan dysfunction in SARS-CoV-2 infection. Beyond the cytokine storm and hemodynamic instability, SARS-CoV-2 might directly induce kidney injury and cause histopathologic characteristics, including acute tubular necrosis, podocytopathy and microangiopathy. The expression of apparatus mediating SARS-CoV-2 entry, including angiotensin-converting enzyme 2, transmembrane protease serine 2 (TMPRSS2) and a disintegrin and metalloprotease 17 (ADAM17), within the renal tubular cells is highly associated with acute kidney injury mediated by SARS-CoV-2. Both entry from the luminal and basolateral sides of the renal tubular cells are the possible routes for COVID-19, and the microthrombi associated with severe sepsis and the dysregulated renin–angiotensin–aldosterone system worsen further renal injury in SARS-CoV-2-associated AKI. In the podocytes of the glomerulus, injured podocyte expressed CD147, which mediated the entry of SARS-CoV-2 and worsen further foot process effacement, which would worsen proteinuria, and the chronic hazard induced by SARS-CoV-2-mediated kidney injury is still unknown. Therefore, the aim of the review is to summarize current evidence on SARS-CoV-2-associated AKI and the possible pathogenesis directly by SARS-CoV-2.
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Chaudhary, Jitendra Kumar, Rohitash Yadav, Pankaj Kumar Chaudhary, Anurag Maurya, Rakesh Roshan, Faizul Azam, Jyoti Mehta, et al. "Host Cell and SARS-CoV-2-Associated Molecular Structures and Factors as Potential Therapeutic Targets." Cells 10, no. 9 (September 15, 2021): 2427. http://dx.doi.org/10.3390/cells10092427.
Full textAbstract:
Coronavirus disease 19 (COVID-19) is caused by an enveloped, positive-sense, single-stranded RNA virus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the realm Riboviria, order Nidovirales, family Coronaviridae, genus Betacoronavirus and the species Severe acute respiratory syndrome-related coronavirus. This viral disease is characterized by a myriad of varying symptoms, such as pyrexia, cough, hemoptysis, dyspnoea, diarrhea, muscle soreness, dysosmia, lymphopenia and dysgeusia amongst others. The virus mainly infects humans, various other mammals, avian species and some other companion livestock. SARS-CoV-2 cellular entry is primarily accomplished by molecular interaction between the virus’s spike (S) protein and the host cell surface receptor, angiotensin-converting enzyme 2 (ACE2), although other host cell-associated receptors/factors, such as neuropilin 1 (NRP-1) and neuropilin 2 (NRP-2), C-type lectin receptors (CLRs), as well as proteases such as TMPRSS2 (transmembrane serine protease 2) and furin, might also play a crucial role in infection, tropism, pathogenesis and clinical outcome. Furthermore, several structural and non-structural proteins of the virus themselves are very critical in determining the clinical outcome following infection. Considering such critical role(s) of the abovementioned host cell receptors, associated proteases/factors and virus structural/non-structural proteins (NSPs), it may be quite prudent to therapeutically target them through a multipronged clinical regimen to combat the disease.
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Upadhyay, Jyoti, Nidhi Tiwari, and Mohd N. Ansari. "Role of inflammatory markers in corona virus disease (COVID-19) patients: A review." Experimental Biology and Medicine 245, no. 15 (July 7, 2020): 1368–75. http://dx.doi.org/10.1177/1535370220939477.
Full textAbstract:
The whole world is locked down due to the outbreak of novel Coronavirus Disease 2019 (nCOVID-19). A novel virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus pandemic 2019. Investigating the role of inflammatory mediators and understanding the virology of nCOVID-19 virus help in designing a rational and effective therapy for this infection. This review provides an overview of the inflammatory mediators activated during nCOVID-19 infection and the pathophysiology of this viral infection. In this review, the authors have a detailed discussion about the types of viral strains of nCOVID-19, its mechanism of action, host immune response, and the dysregulation caused by the viruses in the host immune system causing disease progression. Understanding the role of inflammatory cytokines, chemokines, and clinical immunology will be the approach to find out the possible novel therapeutic interventions. Therapies involving regulation of immune responses help in inhibiting the various steps in the pathologies of infection. Also, updated knowledge regarding the dysregulation of immune system and disease outcome in critically ill patients serves as a precautionary measure in the development and evaluation of vaccine. Impact statement In late 2019, a novel virus called SARS-CoV-2, expanded globally from Wuhan, China and was declared a pandemic on 11 March 2020 by the WHO. The mechanism of virus entry inside the host cell depends upon the cellular proteases including cathepsins, HAT, and TMPRSS2, which splits up the spike protein and causes further penetration. MERS coronavirus uses DPP4, while coronavirus HCoV-NL63 and SARS-CoV and SARS-CoV-2 employ ACE-2 as the key receptor. Cytokine storm syndrome was analyzed in critically ill nCOVID-19 patients and it is presented with high inflammatory mediators, systemic inflammation, and multiple organ failure. Among various inflammatory mediators, the level of interleukins (IL-2, IL-7, IL-10), G-CSF, MIP1A, MCP1, and TNF-α was reported to be higher in critically ill patients. Understanding this molecular mechanism of ILs, T cells, and dendritic cells will be helpful to design immunotherapy and novel drugs for the treatment of nCOVID-19 infection.
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Gupta, Ruchir, Jacob Charron, Cynthia L. Stenger, Jared Painter, Hunter Steward, Taylor W. Cook, William Faber, et al. "SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics." Journal of Biological Chemistry 295, no. 33 (June 25, 2020): 11742–53. http://dx.doi.org/10.1074/jbc.ra120.014873.
Full textAbstract:
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged the speed at which laboratories can discover the viral composition and study health outcomes. The small ∼30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread while enabling a robust understanding of all of the proteins the viral genome encodes. We have employed protein modeling, molecular dynamics simulations, evolutionary mapping, and 3D printing to gain a full proteome- and dynamicome-level understanding of SARS-CoV-2. We established the Viral Integrated Structural Evolution Dynamic Database (VIStEDD at RRID:SCR_018793) to facilitate future discoveries and educational use. Here, we highlight the use of VIStEDD for nsp6, nucleocapsid (N), and spike (S) surface glycoprotein. For both nsp6 and N, we found highly conserved surface amino acids that likely drive protein–protein interactions. In characterizing viral S protein, we developed a quantitative dynamics cross-correlation matrix to gain insights into its interactions with the angiotensin I–converting enzyme 2 (ACE2)–solute carrier family 6 member 19 (SLC6A19) dimer. Using this quantitative matrix, we elucidated 47 potential functional missense variants from genomic databases within ACE2/SLC6A19/transmembrane serine protease 2 (TMPRSS2), warranting genomic enrichment analyses in SARS-CoV-2 patients. These variants had ultralow frequency but existed in males hemizygous for ACE2. Two ACE2 noncoding variants (rs4646118 and rs143185769) present in ∼9% of individuals of African descent may regulate ACE2 expression and may be associated with increased susceptibility of African Americans to SARS-CoV-2. We propose that this SARS-CoV-2 database may aid research into the ongoing pandemic.
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Alvarado, David, Maria Gomez Castro, Naomi Sonnek, Xueyang Cui, Siyuan Ding, and Matthew Ciorba. "INCREASED CATHEPSIN EXPRESSION CORRELATES WITH SARS-COV-2 INFECTION IN HUMAN IBD ENTEROIDS." Inflammatory Bowel Diseases 27, Supplement_1 (January 1, 2021): S26. http://dx.doi.org/10.1093/ibd/izaa347.058.
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Abstract Introduction Coronavirus Disease 2019 (COVID-19) is an ongoing public health crisis that has sickened or precipitated death in millions. The etiologic agent of COVID-19, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), infects the intestinal epithelium, with viral RNA shed in the stool, and can induce GI symptoms similar to the human inflammatory bowel diseases (IBD). An international surveillance epidemiology study, SECURE-IBD, reported that the standardized mortality ratio trends higher in IBD patients (1.5–1.8) and that 5-aminosalicylic acid (5-ASA) therapy correlates with poor outcome. Together these data indicate patients with IBD may represent a particularly vulnerable population during this COVID-19 pandemic. Methods Published datasets GSE75214 and GSE16879 were downloaded and expression levels of select genes were querried using RStudio. Primary human ileal spheroids (enteroids), derived from healthy donors and patients with Crohn’s disease (CD), were grown on 2D transwells until confluent. Cells were then differentiated for 3d before infection with a modified vesicular stomatitis virus expressing the SARS-CoV-2 spike protein (VSV-SARS-CoV-2) and green fluorescent protein (GFP) for 1 h at a multiplicity of infection (MOI) of ~0.5. Healthy enteroids were treated with 10 ng/ml of human Tumor Necrosis Factor alpha (TNF-α) for 24h before infection via the basolateral reservoir or 5-ASA 5h before infection via the apical reservoir. 24h after infection, cells were processed for immunofluorescence or RNA expression of select genes by qRT-PCR. Results VSV-SARS-CoV-2 was able to infect both healthy and CD enteroids as determined by co-staining of GFP, indicative of virus infection, and the viral receptor ACE2. However, levels of GFP fluorescence did not correlate with ACE2 expression in CD enteroids. A subset of CD enteroids exhibited enhanced protease expression (TMPRSS2, TMPRSS4, CTSL), each of which correlated with higher viral RNA levels (P=0.04, P=0.002, P=0.006, respectively). In Vero E6 cells, 5-ASA inhibited the replication of a clinical isolate of SARS-CoV-2 in a concentration-dependent manner. Treating healthy enteroids with 5-ASA did not have any effect on viral proliferation, while TNF-α pretreatment reduced viral RNA. 5-ASA treatment caused a reduction of ACE2 and an increase in CTSL expression. Conclusions Host proteases, particularly the lysosomal protease CTSL, contribute to the infection of CD enteroids and may represent novel therapeutic targets in patients with IBD and COVID-19. 5-ASA modulates the expression of several epithelial genes relevant to SARS-CoV-2 infection, yet does not alter viral replication in healthy enteroids.
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Jankun, Jerzy. "COVID-19 pandemic; transmembrane protease serine 2 (TMPRSS2) inhibitors as potential drugs." Translation: The University of Toledo Journal of Medical Sciences 7 (April 24, 2020): 1–5. http://dx.doi.org/10.46570/utjms.vol7-2020-361.
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Ongoing search for treatment to ease COVID-19 pandemic concentrate on development of a vaccine or medication to prevent and treat this disease. One of the possibilities is developing new antiviral drugs that are aiming at both a virus replication or the host factor(s) that are critical to virus’s replication. Serine proteases, which activate the viral spike glycoproteins and facilitate virus-cell membrane fusions for host cell entry, its replication and spread, are proposed as the potential targets for antiviral drug design. Existing literature is already providing evidence that transmembrane protease serine 2 (TMPRSS2) is one of the promising targets. When inhibited it can slow or stop replication of viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One of the convincing evidences of the critical role of TMPRSS2 in the coronavirus’s replication was provided by animal study. The replication of influenza viruses was inhibited in TMPRSS2(-/-) knockout mice in comparison to wild type (WT) mice, which developed high mortality rate. Existing inhibitors of TMPRSS2 can be divided into two groups. The first include drugs already approved by FDA or other organizations for treatment of different diseases. That include: Camostat (from Japan, produced by Ono Pharmaceutical), aprotinin (Trasylol, produced by Nordic Group Pharmaceuticals) and rimantadine (Flumadine, produced by Forest Pharmaceuticals, Inc.). Existing in vitro, in vivo and some limited human studies show that this type of drugs limit reproduction of coronaviruses and/or prevented the development of viral pneumonia. One study indicated that combined treatment by aprotinin and rimantadine prevented the development of fatal hemorrhagic viral pneumonia, and protected about 75% animals, when the separate administration of aprotinin or rimantadine induced less protection. The second group includes potential drugs not approved for the human use yet. That include plasminogen activator inhibitor type 1 (PAI-1) and recently developed small molecular inhibitors. PAI-1 is a serine protease inhibitor that regulates physiological breakdown of blood clots by inhibiting of tissue (tPA) and urokinase (uPA) plasminogen activators. But PAI-1 is also an effective inhibitor of various membrane-anchored serine proteases including TMPRSS2. It was reported that PAI-1 inhibited trypsin- and TMPRSS2-mediated cleavage of hemagglutinin and suppressed influenza virus in animals. PAI-1 is human in origin and engineered forms with extended half-life were developed and could be an attractive addition to the existing TMPRSS2 inhibitors. And finally, derivatives of sulfonylated 3-amindinophenylalanylamide were found to inhibit TMPRSS2 with a high affinity and efficiently block the influenza virus propagation in human cells. This paper is intended to provide review on possible or hypothetical beneficial effects of (TMPRSS2) inhibitors as one of options to fight infection with Covid-19.
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Abdel Hameid, Reem, Estelle Cormet-Boyaka, Wolfgang M. Kuebler, Mohammed Uddin, and Bakhrom K. Berdiev. "SARS-CoV-2 may hijack GPCR signaling pathways to dysregulate lung ion and fluid transport." American Journal of Physiology-Lung Cellular and Molecular Physiology 320, no. 3 (March 1, 2021): L430—L435. http://dx.doi.org/10.1152/ajplung.00499.2020.
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The tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic, toward the host cells is determined, at least in part, by the expression and distribution of its cell surface receptor, angiotensin-converting enzyme 2 (ACE2). The virus further exploits the host cellular machinery to gain access into the cells; its spike protein is cleaved by a host cell surface transmembrane serine protease 2 (TMPRSS2) shortly after binding ACE2, followed by its proteolytic activation at a furin cleavage site. The virus primarily targets the epithelium of the respiratory tract, which is covered by a tightly regulated airway surface liquid (ASL) layer that serves as a primary defense mechanism against respiratory pathogens. The volume and viscosity of this fluid layer is regulated and maintained by a coordinated function of different transport pathways in the respiratory epithelium. We argue that SARS-CoV-2 may potentially alter evolutionary conserved second-messenger signaling cascades via activation of G protein-coupled receptors (GPCRs) or by directly modulating G protein signaling. Such signaling may in turn adversely modulate transepithelial transport processes, especially those involving cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial Na+ channel (ENaC), thereby shifting the delicate balance between anion secretion and sodium absorption, which controls homeostasis of this fluid layer. As a result, activation of the secretory pathways including CFTR-mediated Cl− transport may overwhelm the absorptive pathways, such as ENaC-dependent Na+ uptake, and initiate a pathophysiological cascade leading to lung edema, one of the most serious and potentially deadly clinical manifestations of COVID-19.
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Tikhonov, Dmitrii, and Vsevolod Vladimirtsev. "COVID-19. SARS-Cov-2 pandemic, transmission pathways, distribution features, and individual susceptibility." Сибирские исследования (Siberian Research) 4, no. 2 (December 15, 2020): 48–60. http://dx.doi.org/10.33384/26587270.2020.04.02.06e.
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In December 2019, an outbreak of pneumonia of unknown etiology was registered in Wuhan, Hubei province of the people's Republic of China. The virus was soon isolated and its genome sequenced. It is called the severe acute respiratory syndrome coronavirus‑2 (SARS-Cov-2, English SARS-Cov-2), and the disease caused by it is coronavirus infection – 19 (English COVID-19). Who recognized the COVID-19 outbreak as a pandemic on March 11. The entire world is currently affected by the pandemic. The first focus of coronavirus infection in Russia was detected on February 27, brought from Europe. The infection reached the most remote corners of Siberia by mid-April. The aim of this study is to analyze the characteristics of SARS-Cov-2, its pathways into the body and individual susceptibility to the virus. Methods and materials. The review of scientific articles on the research topic was based on the analysis of scientific articles on COVID-19. Articles were searched in the Web of Sciences, Scopus, PubMed, and eLIBRARY databases, as well as by article links. Results. The SARS-Cov-2 virus is a single-stranded positive-chain RNA virus from the Coronavirus family (Coronaviridae). According to most researchers, the SARS-Cov-2 virus evolved from bat coronaviruses, with the approximate time of divergence from the nearest bat virus species RaTG13 occurring in 1963. It uses ACE-2 receptors, which are widely present throughout the body, to enter host cells. High virus contagiousness is provided by the acquisition of an additional furin site for cleavage of the spike protein in the form of the amino acid sequence Arg-Arg-Ala-Arg (682RRAR685). This site of the S1 domain of the spike protein can be cleaved by: transmembrane serine protease 2 (TMPRSS2), furin, but also many cellular and extracellular proteases, as well as plasmin(ogen) s. Many ways of cleavage of the spike protein significantly increase the ability of the virus to enter the cell and its contagiousness. The main routes of transmission of SARS-Cov-2 are respiratory drops and close contact. The main entrance gate of the virus is the respiratory tract, may be conjunctiva, likely fecal-oral pathway. The article discusses the skin as an entrance gate. Some skin manifestations of the disease can be caused by this way. The incubation period of COVID-19 lasts on average 5-6 days, while the live infectious virus begins to be released 2-3 days before the first symptoms appear and stops on the 8th day after the symptoms appear, but only in severe patients the virus release can last up to 15 days. Asymptomatic patients may account for 40% of cases. Features of individual susceptibility to COVID-19 and the severity of clinical manifestations may be caused by: 1) the property of allelic variants of the virus and their virulence; 2) the infectious dose of the virus; 3) the use of protective equipment; 4) individual characteristics of the human body; 5) pathogenic mechanisms of infection development. The hypothesis of the protective role of the mumps vaccine explains the phenomenon of extremely low morbidity, asymptomatic or mild infection in children more convincingly. Mass vaccination against mumps in our country began in 1981 (39 years ago), which is probably why children and people under 40 rarely get a severe form of infection in our country. Conclusion. SARS-Cov-2 has pandemic potential and is estimated to be more severe than pandemic influenza viruses. Active isolation of the virus before the onset of symptoms, including by asymptomatic patients (including children), causes the rapid spread of infection and reduces the effectiveness of anti-epidemic measures. The presence of a significant segment of the population with cross-immunity to SARS-Cov-2, including and as a result of vaccination, it is the most likely cause of a high percentage of asymptomatic and mild forms of the disease among children and young people. Effective protection against coronavirus infection in 2019 can only be achieved by taking comprehensive measures to prevent the virus from entering the body through the respiratory tract, per os, conjunctiva and skin, although the latter pathway is not taken into account anywhere in the world. It should be noted that COVID-19 cannot be classified as a particularly dangerous infection, but its high contagiousness, the likelihood of multiple entry gates of the virus into the human body, multi-organ lesions and a high mortality rate of risk groups make it a special infection that requires significant efforts of humanity to eliminate it.
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Rochette, Luc, and Steliana Ghibu. "Mechanics Insights of Alpha-Lipoic Acid against Cardiovascular Diseases during COVID-19 Infection." International Journal of Molecular Sciences 22, no. 15 (July 26, 2021): 7979. http://dx.doi.org/10.3390/ijms22157979.
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Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, in late December 2019. Since then, COVID-19 has spread rapidly worldwide and was declared a global pandemic on 20 March 2020. Cardiovascular complications are rapidly emerging as a major peril in COVID-19 in addition to respiratory disease. The mechanisms underlying the excessive effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with cardiovascular comorbidities remain only partly understood. SARS-CoV-2 infection is caused by binding of the viral surface spike (S) protein to the human angiotensin-converting enzyme 2 (ACE2), followed by the activation of the S protein by transmembrane protease serine 2 (TMPRSS2). ACE2 is expressed in the lung (mainly in type II alveolar cells), heart, blood vessels, small intestine, etc., and appears to be the predominant portal to the cellular entry of the virus. Based on current information, most people infected with SARS-CoV-2 virus have a good prognosis, while a few patients reach critical condition, especially the elderly and those with chronic underlying diseases. The “cytokine storm” observed in patients with severe COVID-19 contributes to the destruction of the endothelium, leading to “acute respiratory distress syndrome” (ARDS), multiorgan failure, and death. At the origin of the general proinflammatory state may be the SARS-CoV-2-mediated redox status in endothelial cells via the upregulation of ACE/Ang II/AT1 receptors pathway or the increased mitochondrial reactive oxygen species (mtROS) production. Furthermore, this vicious circle between oxidative stress (OS) and inflammation induces endothelial dysfunction, endothelial senescence, high risk of thrombosis and coagulopathy. The microvascular dysfunction and the formation of microthrombi in a way differentiate the SARS-CoV-2 infection from the other respiratory diseases and bring it closer to cardiovascular diseases like myocardial infarction and stroke. Due the role played by OS in the evolution of viral infection and in the development of COVID-19 complications, the use of antioxidants as adjuvant therapy seems appropriate in this new pathology. Alpha-lipoic acid (ALA) could be a promising candidate that, through its wide tissue distribution and versatile antioxidant properties, interferes with several signaling pathways. Thus, ALA improves endothelial function by restoring the endothelial nitric oxide synthase activity and presents an anti-inflammatory effect dependent or independent of its antioxidant properties. By improving mitochondrial function, it can sustain the tissues’ homeostasis in critical situation and by enhancing the reduced glutathione it could indirectly strengthen the immune system. This complex analysis could open a new therapeutic perspective for ALA in COVID-19 infection.
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Fisun, A. Ya, D. V. Cherkashin, V. V. Tyrenko, C. V. Zhdanov, and C. V. Kozlov. "Role of renin-angiotensin-aldosterone system in the interaction with coronavirus SARS-CoV-2 and in the development of strategies for prevention and treatment of new coronavirus infection (COVID-19)." "Arterial’naya Gipertenziya" ("Arterial Hypertension") 26, no. 3 (June 25, 2020): 248–62. http://dx.doi.org/10.18705/1607-419x-2020-26-3-248-262.
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The 2019 coronavirus pandemic (COVID-19), due to the new SARS-CoV-2 virus, represents the greatest global public health crisis and an unprecedented challenge to find effective ways to prevent and treat. In the active phase of a pandemic, early results allow these preventive measures to be implemented on a scale compatible with the pandemic. If the results are convincing, their value will be difficult to overestimate, since additional one or two outbreaks of this infection are expected. Clinical data is emerging rapidly from a large number of people afflicted with SARS-CoV-2, which should provide clinicians with accurate evidence of the effectiveness of different preventive and treatment methods. In particular, an active search is underway for cellular mechanisms that SARS-CoV-2 uses to penetrate tissues. These include information about the receptor of the angiotensin-converting enzyme receptor (ACE 2). SARS-CoV-2, a single-stranded envelope RNA virus, attaches to cells via a viral spike (S) protein that binds to the ACE 2. After binding to the receptor, the viral particle uses the receptors of the host cell and endosomes to enter the cells. Human type transmembrane serine protease 2 (TMPRSS 2) facilitates penetration into the cell via protein S. Once inside the cell, viral polyproteins are synthesized that encode the replicate transcriptase complex. The virus then synthesizes RNA through its RNA-dependent RNA polymerase. Structural proteins are synthesized leading to the completion of the assembly and release of viral particles. These stages of the virus life cycle provide potential targets for drug therapy. Current clinical and scientific data do not support discontinuation of ACE inhibitors or angiotensin receptor blockers in patients with COVID-19, and an ongoing discussion is addressed in this review.
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Iwata-Yoshikawa, Naoko, Tadashi Okamura, Yukiko Shimizu, Hideki Hasegawa, Makoto Takeda, and Noriyo Nagata. "TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection." Journal of Virology 93, no. 6 (January 9, 2019). http://dx.doi.org/10.1128/jvi.01815-18.
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ABSTRACT Transmembrane serine protease TMPRSS2 activates the spike protein of highly pathogenic human coronaviruses such as severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV). In vitro, activation induces virus-cell membrane fusion at the cell surface. However, the roles of TMPRSS2 during coronavirus infection in vivo are unclear. Here, we used animal models of SARS-CoV and MERS-CoV infection to investigate the role of TMPRSS2. Th1-prone C57BL/6 mice and TMPRSS2-knockout (KO) mice were used for SARS-CoV infection, and transgenic mice expressing the human MERS-CoV receptor DPP4 (hDPP4-Tg mice) and TMPRSS2-KO hDPP4-Tg mice were used for MERS-CoV infection. After experimental infection, TMPRSS2-deficient mouse strains showed reduced body weight loss and viral kinetics in the lungs. Lack of TMPRSS2 affected the primary sites of infection and virus spread within the airway, accompanied by less severe immunopathology. However, TMPRSS2-KO mice showed weakened inflammatory chemokine and/or cytokine responses to intranasal stimulation with poly(I·C), a Toll-like receptor 3 agonist. In conclusion, TMPRSS2 plays a crucial role in viral spread within the airway of murine models infected by SARS-CoV and MERS-CoV and in the resulting immunopathology. IMPORTANCE Broad-spectrum antiviral drugs against highly pathogenic coronaviruses and other emerging viruses are desirable to enable a rapid response to pandemic threats. Transmembrane protease serine type 2 (TMPRSS2), a protease belonging to the type II transmembrane serine protease family, cleaves the coronavirus spike protein, making it a potential therapeutic target for coronavirus infections. Here, we examined the role of TMPRSS2 using animal models of SARS-CoV and MERS-CoV infection. The results suggest that lack of TMPRSS2 in the airways reduces the severity of lung pathology after infection by SARS-CoV and MERS-CoV. Taken together, the results will facilitate development of novel targets for coronavirus therapy.
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Mauvais-Jarvis, Franck. "Do Anti-androgens Have Potential as Therapeutics for COVID-19?" Endocrinology 162, no. 8 (June 5, 2021). http://dx.doi.org/10.1210/endocr/bqab114.
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Abstract Coronavirus disease 2019 (COVID-19) is characterized by a gender disparity in severity, with men exhibiting higher hospitalization and mortality rates than women. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, infects cells following recognition and attachment of the viral spike glycoprotein to the angiotensin-converting enzyme 2 transmembrane protein, followed by spike protein cleavage and activation by cell surface transmembrane protease serine 2 (TMPRSS2). In prostate cancer cells, androgen acting on the androgen receptor increases TMPRSS2 expression, which has led to the hypothesis that androgen-dependent expression of TMPRSS2 in the lung may increase men’s susceptibility to severe COVID-19 and that, accordingly, suppressing androgen production or action may mitigate COVID-19 severity by reducing SARS-CoV-2 amplification. Several ongoing clinical trials are testing the ability of androgen deprivation therapies or anti-androgens to mitigate COVID-19. This perspective discusses clinical and molecular advances on the rapidly evolving field of androgen receptor (AR) action on cell surface transmembrane protease serine 2 (TMPRSS2) expression and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the potential effect of anti-androgens on coronavirus disease 2019 (COVID-19) severity in male patients. It discusses limitations of current studies and offers insight for future directions.
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Brooke, Greg N., and Filippo Prischi. "Structural and functional modelling of SARS-CoV-2 entry in animal models." Scientific Reports 10, no. 1 (September 28, 2020). http://dx.doi.org/10.1038/s41598-020-72528-z.
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Abstract SARS-CoV-2 is the novel coronavirus responsible for the outbreak of COVID-19, a disease that has spread to over 100 countries and, as of the 26th July 2020, has infected over 16 million people. Despite the urgent need to find effective therapeutics, research on SARS-CoV-2 has been affected by a lack of suitable animal models. To facilitate the development of medical approaches and novel treatments, we compared the ACE2 receptor, and TMPRSS2 and Furin proteases usage of the SARS-CoV-2 Spike glycoprotein in human and in a panel of animal models, i.e. guinea pig, dog, cat, rat, rabbit, ferret, mouse, hamster and macaque. Here we showed that ACE2, but not TMPRSS2 or Furin, has a higher level of sequence variability in the Spike protein interaction surface, which greatly influences Spike protein binding mode. Using molecular docking simulations we compared the SARS-CoV and SARS-CoV-2 Spike proteins in complex with the ACE2 receptor and showed that the SARS-CoV-2 Spike glycoprotein is compatible to bind the human ACE2 with high specificity. In contrast, TMPRSS2 and Furin are sufficiently similar in the considered hosts not to drive susceptibility differences. Computational analysis of binding modes and protein contacts indicates that macaque, ferrets and hamster are the most suitable models for the study of inhibitory antibodies and small molecules targeting the SARS-CoV-2 Spike protein interaction with ACE2. Since TMPRSS2 and Furin are similar across species, our data also suggest that transgenic animal models expressing human ACE2, such as the hACE2 transgenic mouse, are also likely to be useful models for studies investigating viral entry.
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Schönfelder, Kristina, Katharina Breuckmann, Carina Elsner, Ulf Dittmer, David Fistera, Frank Herbstreit, Joachim Risse, et al. "Transmembrane serine protease 2 Polymorphisms and Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Type 2 Infection: A German Case-Control Study." Frontiers in Genetics 12 (April 21, 2021). http://dx.doi.org/10.3389/fgene.2021.667231.
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The transmembrane serine protease 2 (TMPRSS2) is the major host protease that enables entry of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) into host cells by spike (S) protein priming. Single nucleotide polymorphisms (SNPs) in the gene TMPRSS2 have been associated with susceptibility to and severity of H1N1 or H1N9 influenza A virus infections. Functional variants may influence SARS-CoV-2 infection risk and severity of Coronavirus disease 2019 (COVID-19) as well. Therefore, we analyzed the role of SNPs in the gene TMPRSS2 in a German case-control study. We performed genotyping of the SNPs rs2070788, rs383510, and rs12329760 in the gene TMPRSS2 in 239 SARS-CoV-2-positive and 253 SARS-CoV-2-negative patients. We analyzed the association of the SNPs with susceptibility to SARS-CoV-2 infection and severity of COVID-19. SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding their demographics. The CC genotype of TMPRSS2 rs383510 was associated with a 1.73-fold increased SARS-CoV-2 infection risk, but was not correlated to severity of COVID-19. Neither TMPRSS2 rs2070788 nor rs12329760 polymorphisms were related to SARS-CoV-2 infection risk or severity of COVID-19. In a multivariable analysis (MVA), the rs383510 CC genotype remained an independent predictor for a 2-fold increased SARS-CoV-2 infection risk. In summary, our report appears to be the first showing that the intron variant rs383510 in the gene TMPRSS2 is associated with an increased risk to SARS-CoV-2 infection in a German cohort.
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Wettstein, Lukas, Tatjana Weil, Carina Conzelmann, Janis A. Müller, Rüdiger Groß, Maximilian Hirschenberger, Alina Seidel, et al. "Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection." Nature Communications 12, no. 1 (March 19, 2021). http://dx.doi.org/10.1038/s41467-021-21972-0.
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AbstractSARS-CoV-2 is a respiratory pathogen and primarily infects the airway epithelium. As our knowledge about innate immune factors of the respiratory tract against SARS-CoV-2 is limited, we generated and screened a peptide/protein library derived from bronchoalveolar lavage for inhibitors of SARS-CoV-2 spike-driven entry. Analysis of antiviral fractions revealed the presence of α1-antitrypsin (α1AT), a highly abundant circulating serine protease inhibitor. Here, we report that α1AT inhibits SARS-CoV-2 entry at physiological concentrations and suppresses viral replication in cell lines and primary cells including human airway epithelial cultures. We further demonstrate that α1AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein α1AT is an inhibitor of TMPRSS2 and SARS-CoV-2 entry, and may play an important role in the innate immune defense against the novel coronavirus. Our findings suggest that repurposing of α1AT-containing drugs has prospects for the therapy of COVID-19.
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Chen, Zhaohui, Junyi Hu, Lilong Liu, Rong Chen, Miao Wang, Ming Xiong, Zhen-Qiong Li, et al. "SARS-CoV-2 Causes Acute Kidney Injury by Directly Infecting Renal Tubules." Frontiers in Cell and Developmental Biology 9 (May 31, 2021). http://dx.doi.org/10.3389/fcell.2021.664868.
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Acute kidney injury (AKI) is one of the most prevalent complications among hospitalized coronavirus disease 2019 (COVID-19) patients. Here, we aim to investigate the causes, risk factors, and outcomes of AKI in COVID-19 patients. We found that angiotensin-converting enzyme II (ACE2) and transmembrane protease serine 2 (TMPRSS2) were mainly expressed by different cell types in the human kidney. However, in autopsy kidney samples, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein was detected in ACE2+ or TMPRSS2+ renal tubular cells, whereas the RNAscope® Assay targeting the SARS-CoV-2 Spike gene was positive mainly in the distal tubular cells and seldom in the proximal tubular cells. In addition, the TMPRSS2 and kidney injury marker protein levels were significantly higher in the SARS-CoV-2-infected renal distal tubular cells, indicating that SARS-CoV-2-mediated AKI mainly occurred in the renal distal tubular cells. Subsequently, a cohort analysis of 722 patients with COVID-19 demonstrated that AKI was significantly related to more serious disease stages and poor prognosis of COVID-19 patients. The progressive increase of blood urea nitrogen (BUN) level during the course of COVID-19 suggests that the patient’s condition is aggravated. These results will greatly increase the current understanding of SARS-CoV-2 infection.
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Kreutzberger, Alex J. B., Anwesha Sanyal, Ravi Ojha, Jesse D. Pyle, Olli Vapalahti, Giuseppe Balistreri, and Tom Kirchhausen. "Synergistic block of SARS-CoV-2 infection by combined drug inhibition of the host entry factors PIKfyve kinase and TMPRSS2 protease." Journal of Virology, August 18, 2021. http://dx.doi.org/10.1128/jvi.00975-21.
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Repurposing FDA-approved inhibitors able to prevent infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could provide a rapid path to establish new therapeutic options to mitigate the effects of coronavirus disease 2019 (COVID-19). Proteolytic cleavages of the spike S protein of SARS-CoV-2, mediated by the host cell proteases cathepsin and TMPRSS2, alone or in combination, are key early activation steps required for efficient infection. The PIKfyve kinase inhibitor apilimod interferes with late endosomal viral traffic, and through an ill-defined mechanism prevents in vitro infection through late endosomes mediated by cathepsin. Similarly, inhibition of TMPRSS2 protease activity by camostat mesylate or nafamostat mesylate prevents infection mediated by the TMPRSS2-dependent and cathepsin-independent pathway. Here, we combined the use of apilimod with camostat mesylate or nafamostat mesylate and found an unexpected ∼5-10-fold increase in their effectiveness to prevent SARS-CoV-2 infection in different cell types. Comparable synergism was observed using both, a chimeric vesicular stomatitis virus (VSV) containing S of SARS-CoV-2 (VSV-SARS-CoV-2) and SARS-CoV-2 virus. The substantial ∼5-fold or more decrease of half maximal effective concentrations (EC 50 values) suggests a plausible treatment strategy based on the combined use of these inhibitors. IMPORTANCE Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the coronavirus disease 2019 (COVID-2019) global pandemic. There are ongoing efforts to uncover effective antiviral agents that could mitigate the severity of the disease by controlling the ensuing viral replication. Promising candidates include small molecules that inhibit the enzymatic activities of host proteins, thus preventing SARS-CoV-2 entry and infection. They include Apilimod, an inhibitor of PIKfyve kinase and camostat mesylate and nafamostat mesylate, inhibitors of TMPRSS2 protease. Our research is significant for having uncovered an unexpected synergism in the effective inhibitory activity of apilimod used together with camostat mesylate or with nafamostat mesylate.
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Motohashi, Noboru, Anuradha Vanam, and Rao Gollapudi. "In Silico Study of Curcumin and Folic Acid as Potent Inhibitors of Human Transmembrane Protease Serine 2 in the Treatment of COVID-19." INNOSC Theranostics and Pharmacological Sciences, October 16, 2020, 3–9. http://dx.doi.org/10.36922/itps.v3i2.935.
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Background. Human transmembrane protease 2 (TMPRSS2) protein is essential for priming spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in association with human angiotensin-converting enzyme 2 (ACE2) surface receptor to facilitate viral invasion into host human cell through ACE2 receptor. Impeding TMPRSS2 protein activity is currently a preferred choice of the treatment of coronavirus disease 2019 (COVID-19) which is caused by SARS-CoV-2. Curcumin and folic acid are potential candidates for inhibiting TMPRSS2. Objective. The present study aimed to demonstrate the inhibitory activities of curcumin and folic acid, along with known human serine protease inhibitors such as nafamostat and camostat, on TMPRSS2. Methods. Curcumin and folic acid, along with nafamostat and camostat, were docked on a modeled human TMPRSS2 protein 3D structure. Nafamostat and curcumin interactions with targeted TMPRSS2 protein were identical whereas camostat and folic acid displayed similar interactions. Results. The hydrogen bond (H-bond) energies of docked curcumin, folic acid, nafamostat, and camostat were −19.86 kJ/mol, −17.63 kJ/mol, −10.53 kJ/mol, and −14.41 kJ/mol, respectively. Higher H-bond energies could strengthen protein-ligand interactions. Our results showed binding site similarities between curcumin and nafamostat as well as folic acid and camostat. Conclusion. The current in silico simulation suggested that curcumin and folic acid displayed binding poses with TMPRSS2 which are similar to nafamostat and camostat. Therefore, curcumin and folic acid could emerge as potential drug candidates to control COVID-19.
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Tavakoli Far, Fateme, and Ehsan Amiri-Ardekani. "SPIKE PROTEIN AND ITS PROTEASES ROLE IN SARS-COV-2 PATHOGENICITY AND TREATMENT; A REVIEW." Proceedings of the Shevchenko Scientific Society. Medical Sciences 64, no. 1 (June 29, 2021). http://dx.doi.org/10.25040/ntsh2021.01.05.
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Since December 2019, a novel beta coronavirus has spread around the world. This virus can cause severe acute respiratory syndrome (SARS). In this study, we reviewed proteases of SARS-CoV-2 based on related articles published in journals indexed by Scopus, PubMed, and Google Scholar from December 2019 to April 2020. Based on this study, we can claim that this coronavirus has about 76% genotype similarity to SARS coronavirus (SARS-CoV). Also, similarities between these two viruses have been found in the mechanism of entry into host cells and pathogenicity. ACE 2, the angiotensin convertase enzyme 2, plays a role in the Renin-Angiotensin-Aldosterone system (RAAS) and blood pressure regulation. Some mechanisms have been reported for the role of ACE 2 in the pathogenicity of SARS-CoV-2. For example, the interaction between the ACE 2 receptor and spike protein mediated by TMPRSS2, Cathepsin B/L, and other enzymes is responsible for the entry of the virus into human cells and pathogenicity. Some host cell endosomal enzymes are necessary to cleavage coronavirus spike protein and cause binding to their common receptor. So, we conclude that molecules like antibodies or small molecules like ACE 2 antagonists and soluble ACE 2 can be used as a good therapeutic candidate to prevent SARS-CoV-2.
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Sacconi, Andrea, Sara Donzelli, Claudio Pulito, Stefano Ferrero, Francesca Spinella, Aldo Morrone, Marta Rigoni, et al. "TMPRSS2, a SARS-CoV-2 internalization protease is downregulated in head and neck cancer patients." Journal of Experimental & Clinical Cancer Research 39, no. 1 (September 23, 2020). http://dx.doi.org/10.1186/s13046-020-01708-6.
Full textAbstract:
Abstract Background SARS-coronavirus-2 enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. We aim to assess differences in both ACE2 and TMPRSS2 expression in normal tissues from oral cavity, pharynx, larynx and lung tissues as well as neoplastic tissues from the same areas. Methods The study has been conducted using the TCGA and the Regina Elena Institute databases and validated by experimental model in HNSCC cells. We also included data from one COVID19 patient who went under surgery for HNSCC. Results TMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues. It was more evident in women than in men, in TP53 mutated versus wild TP53 tumors, in HPV negative patients compared to HPV positive counterparts. Functionally, we modeled the multivariate effect of TP53, HPV, and other inherent variables on TMPRSS2. All variables had a statistically significant independent effect on TMPRSS2. In particular, in tumor tissues, HPV negative, TP53 mutated status and elevated TP53-dependent Myc-target genes were associated with low TMPRSS2 expression. The further analysis of both TCGA and our institutional HNSCC datasets identified a signature anti-correlated to TMPRSS2. As proof-of-principle we also validated the anti-correlation between microRNAs and TMPRSS2 expression in a SARS-CoV-2 positive HNSCC patient tissues Finally, we did not find TMPRSS2 promoter methylation. Conclusions Collectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection due to reduced expression of TMPRSS2. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.