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Journal articles on the topic 'Inhibition covalente'

Author: Grafiati

Published: 8 June 2024

Last updated: 31 July 2025

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1

Zimmer, Collin, Jan Brauer, Dorota Ferenc, et al. "Substitution-Induced Mechanistic Switching in SNAr-Warheads for Cysteine Proteases." Molecules 29, no. 11 (2024): 2660. http://dx.doi.org/10.3390/molecules29112660.

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The aim of this study was to investigate the transition from non-covalent reversible over covalent reversible to covalent irreversible inhibition of cysteine proteases by making delicate structural changes to the warhead scaffold. To this end, dipeptidic rhodesain inhibitors with different N-terminal electrophilic arenes as warheads relying on the SNAr mechanism were synthesized and investigated. Strong structure–activity relationships of the inhibition potency, the degree of covalency, and the reversibility of binding on the arene substitution pattern were found. The studies were complemented

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2

Ma, Xingchuan. "Abstract 4462: Covalent inhibition of eIF4E: A computational approach." Cancer Research 85, no. 8_Supplement_1 (2025): 4462. https://doi.org/10.1158/1538-7445.am2025-4462.

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Abstract Covalent docking has emerged as a promising strategy for targeting challenging protein residues. Specifically, lysine residues, which are often overlooked due to their lower nucleophilicity compared to cysteines, have shown potential in the development of covalent inhibitors for eukaryotic translation initiation factor 4E (eIF4E), a critical regulator of protein synthesis implicated in breast cancers. Leveraging aryl sulfonyl fluorides, recent studies had successfully docked to K162 within eIF4E and shown reduced protein activity, but the molecules had faced significant specificity an

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Aljoundi, Aimen, Ahmed El Rashedy, Patrick Appiah-Kubi та Mahmoud E. S. Soliman. "Coupling of HSP72 α-Helix Subdomains by the Unexpected Irreversible Targeting of Lysine-56 over Cysteine-17; Coevolution of Covalent Bonding". Molecules 25, № 18 (2020): 4239. http://dx.doi.org/10.3390/molecules25184239.

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Covalent inhibition has recently gained a resurgence of interest in several drug discovery areas. The expansion of this approach is based on evidence elucidating the selectivity and potency of covalent inhibitors when bound to particular amino acids of a biological target. The unexpected covalent inhibition of heat shock protein 72 (HSP72) by covalently targeting Lys-56 instead of Cys-17 was an interesting observation. However, the structural basis and conformational changes associated with this preferential coupling to Lys-56 over Cys-17 remain unclear. To resolve this mystery, we employed st

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Peng, Huayong, Chenliang Chu, Lu Jin, et al. "Study on Oleum cinnamomi Inhibiting Cutibacterium acnes and Its Covalent Inhibition Mechanism." Molecules 29, no. 13 (2024): 3165. http://dx.doi.org/10.3390/molecules29133165.

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Oleum cinnamomi (OCM) is a volatile component of the Cinnamomum cassia Presl in the Lauraceae family, which displays broad-spectrum antibacterial properties. It has been found that OCM has a significant inhibitory effect against Cutibacterium acnes (C. acnes), but the precise target and molecular mechanism are still not fully understood. In this study, the antibacterial activity of OCM against C. acnes and its potential effect on cell membranes were elucidated. Metabolomics methods were used to reveal metabolic pathways, and proteomics was used to explore the targets of OCM inhibiting C. acnes

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Liu, S. Q., and P. A. Knauf. "Lys-430, site of irreversible inhibition of band 3 Cl- flux by eosin-5-maleimide, is not at the transport site." American Journal of Physiology-Cell Physiology 264, no. 5 (1993): C1155—C1164. http://dx.doi.org/10.1152/ajpcell.1993.264.5.c1155.

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Although eosin-5-maleimide (EM) covalently labels band 3 and has been thought to react at the external-facing anion transport site, EM reversibly inhibits Cl- exchange at 0 degrees C in a noncompetitive fashion, indicating that under these conditions it does not bind to the transport site [Knauf, P.A., N.M. Strong, J. Penikas, R.B. Wheeler, Jr., and S.J. Liu. Am. J. Physiol. 264 (Cell Physiol. 33): C1144-C1154 1993]. To see whether or not the covalent labeling by EM takes place at the same noncompetitive site as the reversible binding, we examined the dependence of reaction rate on EM concentr

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Yang, Jianhong, Yong Li, Wei Yan та ін. "Covalent modification of Cys-239 in β-tubulin by small molecules as a strategy to promote tubulin heterodimer degradation". Journal of Biological Chemistry 294, № 20 (2019): 8161–70. http://dx.doi.org/10.1074/jbc.ra118.006325.

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Clinical microtubule-targeting drugs are functionally divided into microtubule-destabilizing and microtubule-stabilizing agents. Drugs from both classes achieve microtubule inhibition by binding different sites on tubulin and inhibiting or promoting polymerization with no concomitant effects on the protein levels of tubulin heterodimers. Here, we have identified a series of small molecules with diverse structures potentially representing a third class of novel tubulin inhibitors that promote degradation by covalent binding to Cys-239 of β-tubulin. The small molecules highlighted in this study

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Maksimenko, A. V., and R. Sh Beabealashvili. "Theoretical Grounding and Formation of Experimental Approaches to Hyaluronidase Structure Consolidation due to Its Computational Interactions with Shortchain Glycosaminoglycan Ligands." Биоорганическая химия 49, no. 4 (2023): 369–83. http://dx.doi.org/10.31857/s0132342323020161.

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The computational study of 3D model hyaluronidase interaction with shortchain glycosaminoglycan ligands demonstrated the diversity and significance of their reaction on enzyme structure. It has been realized due to electrostatic noncovalent interactions (without specific coupling with active site) inducing the perceptible conformational alterations of biocatalyst molecule. As a result of this the inactivation and stabilization of enzyme globule are observed, change of inhibition of biocatalyst by heparin. The binding of chondroitin trimers (on centers cn6, cn3, cn1) to hyaluronidase molecular

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Bhatia, Sumeena, Steven C. Almo, Stanley G. Nathenson, and Richard J. Hodes. "Dynamic equilibrium of B7-1 dimers and monomers is important for regulation of TCR/CD28 – mediated T cell activation (33.28)." Journal of Immunology 182, no. 1_Supplement (2009): 33.28. http://dx.doi.org/10.4049/jimmunol.182.supp.33.28.

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Abstract Under steady state conditions, B7-1 is present as a mixed population of non-covalent dimers and monomers on the cell surface. Here we have examined the physiological significance of this unique dimer-monomer equilibrium state of B7-1. We demonstrate that altering B7-1 to uniformly covalent dimeric state results in increased frequency of CD28 mediated T cell-APC conjugates. This augmented T cell-APC conjugate formation correlates with persistent concentration of signaling molecules, PKC-θ and lck, at the immunological synapse (IS) and with a higher calcium flux in T cells. In contrast,

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Kuznetsova, Anastasiya, Philipp Klein, and Till Opatz. "Halogenated 2,1,3-benzoxadiazoles as Potential Fluorescent Warheads for Covalent Protease Inhibitors." Proceedings 9, no. 1 (2018): 54. http://dx.doi.org/10.3390/ecsoc-22-05670.

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Recently there has been a growing interest in covalent protease inhibitors in both industry and academia, caused by their longer residence times, their higher potency and their high ligand efficiency. Covalently reactive moieties which interact with activated amino acid residues such as serine or cysteine in enzymes like proteases or esterases mostly act through nucleophilic addition, substitution or ring opening. In contrast, nucleophilic aromatic substitution (SNAr) is rarely employed. In our previous work, we prepared and investigated electrophilic “warheads”, which contain aromatic, hetero

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10

Bisconte, Angelina, Ronald Hill, Michael Bradshaw, et al. "Efficacy in collagen induced arthritis models with a selective, reversible covalent Bruton’s tyrosine kinase inhibitor PRN473 is driven by durable target occupancy rather than extended plasma exposure (THER5P.904)." Journal of Immunology 194, no. 1_Supplement (2015): 139.6. http://dx.doi.org/10.4049/jimmunol.194.supp.139.6.

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Abstract Bruton’s Tyrosine Kinase (BTK) is an essential signaling element downstream of the B-cell receptor (BCR). Inhibition of BTK activity in B cells produces phenotypic changes consistent with blockade of the BCR, including inhibition of cell proliferation, differentiation, maturation, and survival. A selective BTK inhibitor has the potential to treat diseases involving inflammation and autoimmunity. Using Principia Biopharma’s proprietary Tailored Covalency™ technology, we discovered PRN473, a reversible covalent BTK inhibitor that selectively binds BTK with a slow off-rate as assessed in

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11

Hognon, Cécilia, Marco Marazzi, and Cristina García-Iriepa. "Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease." International Journal of Molecular Sciences 23, no. 10 (2022): 5855. http://dx.doi.org/10.3390/ijms23105855.

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Inhibition of the papain-like protease (PLpro) of SARS-CoV-2 has been demonstrated to be a successful target to prevent the spreading of the coronavirus in the infected body. In this regard, covalent inhibitors, such as the recently proposed VIR251 ligand, can irreversibly inactivate PLpro by forming a covalent bond with a specific residue of the catalytic site (Cys111), through a Michael addition reaction. An inhibition mechanism can therefore be proposed, including four steps: (i) ligand entry into the protease pocket; (ii) Cys111 deprotonation of the thiol group by a Brønsted–Lowry base; (i

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12

Beck, Philipp, Christian Dubiella, and Michael Groll. "Covalent and non-covalent reversible proteasome inhibition." Biological Chemistry 393, no. 10 (2012): 1101–20. http://dx.doi.org/10.1515/hsz-2012-0212.

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Abstract The 20S proteasome core particle (CP) is the proteolytically active key element of the ubiquitin proteasome system that directs the majority of intracellular protein degradation in eukaryotic cells. Over the past decade, the CP has emerged as an anticancer therapy target after approval of the first-in-class drug bortezomib (Velcade®) by the US Food and Drug Administration. However, bortezomib and all second-generation CP inhibitors that are currently explored in clinical phase studies react covalently and most often irreversibly with the proteolytic sites of the CP, hereby causing per

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13

Piestrzeniewicz, Mariola K., Dorota Wilmańska, Janusz Szemraj, Kazimierz Studzian, and Marek Gniazdowski. "Interactions of Novel Morpholine and Hexamethylene Derivatives of Anthracycline Antibiotics with DNA." Zeitschrift für Naturforschung C 59, no. 9-10 (2004): 739–48. http://dx.doi.org/10.1515/znc-2004-9-1020.

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Abstract Doxorubicin (DOX), daunorubicin (DRB), epidoxorubicin (EDOX) and their analogues with a 3′-NH2 group in daunosamine form a covalent bond with a 2-NH2 group of guanine via a methylene group from formaldehyde (CH2O). It is assumed that a Schiff base type intermediate is formed between CH2O and the 3′-NH2 group in the reaction. This reaction is supposed to occur in the cell. New analogues of anthracyclines with formamidine functionality bound to C-3′ of daunosamine and containing the bulky morpholine (DRBM, DOXM and EDOXM) or hexamethyleneimine rings attached are studied in our laborator

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14

Müller, Patrick, Mergim Meta, Jan Laurenz Meidner, et al. "Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity Study." International Journal of Molecular Sciences 24, no. 8 (2023): 7226. http://dx.doi.org/10.3390/ijms24087226.

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Covalent peptidomimetic protease inhibitors have gained a lot of attention in drug development in recent years. They are designed to covalently bind the catalytically active amino acids through electrophilic groups called warheads. Covalent inhibition has an advantage in terms of pharmacodynamic properties but can also bear toxicity risks due to non-selective off-target protein binding. Therefore, the right combination of a reactive warhead with a well-suited peptidomimetic sequence is of great importance. Herein, the selectivities of well-known warheads combined with peptidomimetic sequences

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15

Gerling, Katharina, Sabrina Ölschläger, Meltem Avci-Adali, et al. "A Novel C1-Esterase Inhibitor Oxygenator Coating Prevents FXII Activation in Human Blood." Biomolecules 10, no. 7 (2020): 1042. http://dx.doi.org/10.3390/biom10071042.

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The limited hemocompatibility of currently used oxygenator membranes prevents long-term use of artificial lungs in patients with lung failure. To improve hemocompatibility, we developed a novel covalent C1-esterase inhibitor (C1-INH) coating. Besides complement inhibition, C1-INH also prevents FXII activation, a very early event of contact phase activation at the crossroads of coagulation and inflammation. Covalently coated heparin, as the current anticoagulation gold standard, served as control. Additionally, a combination of both coatings (C1-INH/heparin) was established. The coatings were t

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Stellmacher, Lena, Tatyana Sandalova, Sarah Schneider, Gunter Schneider, Georg A. Sprenger, and Anne K. Samland. "Novel mode of inhibition byD-tagatose 6-phosphate through a Heyns rearrangement in the active site of transaldolase B variants." Acta Crystallographica Section D Structural Biology 72, no. 4 (2016): 467–76. http://dx.doi.org/10.1107/s2059798316001170.

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Transaldolase B (TalB) and D-fructose-6-phosphate aldolase A (FSAA) fromEscherichia coliare C—C bond-forming enzymes. Using kinetic inhibition studies and mass spectrometry, it is shown that enzyme variants of FSAA and TalB that exhibit D-fructose-6-phosphate aldolase activity are inhibited covalently and irreversibly by D-tagatose 6-phosphate (D-T6P), whereas no inhibition was observed for wild-type transaldolase B fromE. coli. The crystal structure of the variant TalBF178Ywith bound sugar phosphate was solved to a resolution of 1.46 Å and revealed a novel mode of covalent inhibition. The sug

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17

Rao, AK, and MA Kowalska. "ADP-induced platelet shape change and mobilization of cytoplasmic ionized calcium are mediated by distinct binding sites on platelets: 5'- p-fluorosulfonylbenzoyladenosine is a weak platelet agonist." Blood 70, no. 3 (1987): 751–56. http://dx.doi.org/10.1182/blood.v70.3.751.751.

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Abstract Platelet stimulation with ADP results in several responses, including shape change, increase in cytoplasmic ionized calcium concentration [Ca2+]i, an inhibition of adenylate cyclase. 5′-p-Fluorosulphonyl benzoyladenosine (FSBA), which covalently labels an ADP binding site on platelets, blocks platelet shape change but not the inhibition of cyclic AMP levels by ADP, whereas p-chloromercuribenzenesulfonate (pCMBS), a nonpenetrating thiol reagent, has the opposite effects. We examined the effect of FSBA and pCMBS on ADP-induced increase in [Ca2+]i using platelets loaded with fluorescent

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Rao, AK, and MA Kowalska. "ADP-induced platelet shape change and mobilization of cytoplasmic ionized calcium are mediated by distinct binding sites on platelets: 5'- p-fluorosulfonylbenzoyladenosine is a weak platelet agonist." Blood 70, no. 3 (1987): 751–56. http://dx.doi.org/10.1182/blood.v70.3.751.bloodjournal703751.

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Platelet stimulation with ADP results in several responses, including shape change, increase in cytoplasmic ionized calcium concentration [Ca2+]i, an inhibition of adenylate cyclase. 5′-p-Fluorosulphonyl benzoyladenosine (FSBA), which covalently labels an ADP binding site on platelets, blocks platelet shape change but not the inhibition of cyclic AMP levels by ADP, whereas p-chloromercuribenzenesulfonate (pCMBS), a nonpenetrating thiol reagent, has the opposite effects. We examined the effect of FSBA and pCMBS on ADP-induced increase in [Ca2+]i using platelets loaded with fluorescent Ca2+ indi

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19

Betori, Rick C., Yue Liu, Rama K. Mishra, Scott B. Cohen, Stephen J. Kron, and Karl A. Scheidt. "Targeted Covalent Inhibition of Telomerase." ACS Chemical Biology 15, no. 3 (2020): 706–17. http://dx.doi.org/10.1021/acschembio.9b00945.

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20

Ghosh, Avick Kumar, Indranil Samanta, Anushree Mondal, and Wenshe Ray Liu. "Covalent Inhibition in Drug Discovery." ChemMedChem 14, no. 9 (2019): 889–906. http://dx.doi.org/10.1002/cmdc.201900107.

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Kilbourn, R., and G. Lopez-Berestein. "Protease inhibitors block the macrophage-mediated inhibition of tumor cell mitochondrial respiration." Journal of Immunology 144, no. 3 (1990): 1042–45. http://dx.doi.org/10.4049/jimmunol.144.3.1042.

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Abstract The antitumor activity of activated macrophages toward tumor cells, in vitro, appears to involve the production of toxic nitrogen intermediates. These intermediates, particularly nitric oxide, have been shown to cause the inhibition of cell division and to decrease cellular respiration by inhibiting electron transport. We studied the effects of proteolytic inhibitors on macrophage-mediated inhibition of L1210 tumor cell respiration and DNA synthesis, and found that chloromethyl ketone derivatives, which covalently modify serine proteases, can block macrophage cytotoxicity. Furthermore

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Bjij, Imane, Fisayo A. Olotu, Clement Agoni, et al. "Covalent Inhibition in Drug Discovery: Filling the Void in Literature." Current Topics in Medicinal Chemistry 18, no. 13 (2018): 1135–45. http://dx.doi.org/10.2174/1568026618666180731161438.

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The serendipitous discovery of covalent inhibitors and their characteristic potency of inducing irreversible and complete inhibition in therapeutic targets have caused a paradigm shift from the use of non-covalent drugs in disease treatment. This has caused a significant evolution in the field of covalent targeting to understand their inhibitory mechanisms and facilitate the systemic design of novel covalent modifiers for ‘undruggable’ targets. Computational techniques have evolved over the years and have significantly contributed to the process of drug discovery by mirroring the pattern of bi

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23

Strelow, John M. "A Perspective on the Kinetics of Covalent and Irreversible Inhibition." SLAS DISCOVERY: Advancing the Science of Drug Discovery 22, no. 1 (2016): 3–20. http://dx.doi.org/10.1177/1087057116671509.

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The clinical and commercial success of covalent drugs has prompted a renewed and more deliberate pursuit of covalent and irreversible mechanisms within drug discovery. A covalent mechanism can produce potent inhibition in a biochemical, cellular, or in vivo setting. In many cases, teams choose to focus on the consequences of the covalent event, defined by an IC50 value. In a biochemical assay, the IC50 may simply reflect the target protein concentration in the assay. What has received less attention is the importance of the rate of covalent modification, defined by kinact/KI. The kinact/KI is

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Tian, Yafeng, Mi Zhang, Panpan Heng, Hua Hou, and Baoshan Wang. "Computational Investigations on Reaction Mechanisms of the Covalent Inhibitors Ponatinib and Analogs Targeting the Extracellular Signal-Regulated Kinases." International Journal of Molecular Sciences 24, no. 20 (2023): 15223. http://dx.doi.org/10.3390/ijms242015223.

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As an important cancer therapeutic target, extracellular signal-regulated kinases (ERK) are involved in triggering various cellular responses in tumors. Regulation of the ERK signaling pathway by the small molecular inhibitors is highly desired for the sake of cancer therapy. In contrast to the routine inhibitors targeting ERKs through long-range non-bonding interactions, Ponatinib, a covalent inhibitor to ERK2 with a macrocyclic structure characterized by the α,β-C=C unsaturated ketone, can form the stable -C(S)-C(H)-type complex via the four-center barrier due to the nucleophilic addition re

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Colman, RW, WR Figures, LM Scearce, AM Strimpler, FX Zhou, and AK Rao. "Inhibition of collagen-induced platelet activation by 5'-p- fluorosulfonylbenzoyl adenosine: evidence for an adenosine diphosphate requirement and synergistic influence of prostaglandin endoperoxides." Blood 68, no. 2 (1986): 565–70. http://dx.doi.org/10.1182/blood.v68.2.565.565.

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Abstract The relative roles of platelet autacoids such as adenosine diphosphate (ADP), prostaglandin endoperoxides, and thromboxane A2 (TXA2) in collagen-induced platelet activation are not fully understood. We reexamined this relationship using the ADP affinity analogue, 5'-p- fluorosulfonylbenzoyl adenosine (FSBA), which covalently modifies a receptor for ADP on the platelet surface, thereby inhibiting ADP- induced platelet activation. Collagen-induced shape change, aggregation, and fibrinogen binding were each fully inhibited under conditions in which FSBA is covalently incorporated and cou

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Colman, RW, WR Figures, LM Scearce, AM Strimpler, FX Zhou, and AK Rao. "Inhibition of collagen-induced platelet activation by 5'-p- fluorosulfonylbenzoyl adenosine: evidence for an adenosine diphosphate requirement and synergistic influence of prostaglandin endoperoxides." Blood 68, no. 2 (1986): 565–70. http://dx.doi.org/10.1182/blood.v68.2.565.bloodjournal682565.

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The relative roles of platelet autacoids such as adenosine diphosphate (ADP), prostaglandin endoperoxides, and thromboxane A2 (TXA2) in collagen-induced platelet activation are not fully understood. We reexamined this relationship using the ADP affinity analogue, 5'-p- fluorosulfonylbenzoyl adenosine (FSBA), which covalently modifies a receptor for ADP on the platelet surface, thereby inhibiting ADP- induced platelet activation. Collagen-induced shape change, aggregation, and fibrinogen binding were each fully inhibited under conditions in which FSBA is covalently incorporated and could not be

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27

Stevic, Ivan, Howard H. W. Chan, Ankush Chander, Leslie R. Berry, and Anthony K. C. Chan. "Covalently linking heparin to antithrombin enhances prothrombinase inhibition on activated platelets." Thrombosis and Haemostasis 109, no. 06 (2013): 1016–24. http://dx.doi.org/10.1160/th12-10-0766.

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SummaryFactor (F)Xa within the prothrombinase complex is protected from inhibition by unfractionated heparin (UFH), enoxaparin and fondaparinux. We have developed a covalent antithrombin-heparin complex (ATH) with enhanced anticoagulant activity. We have also demonstrated that ATH is superior at inhibiting coagulation factors when assembled on artificial surfaces. The objective of the present study is to determine the ability of ATH vs AT+UFH to inhibit FXa within the prothrombinase complex when the enzyme complex is assembled on the more native platelet system. Discontinuous inhibition assays

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Zhou, X. Edward, Kelly Suino-Powell, Chad R. Schultz, et al. "Structural basis of binding and inhibition of ornithine decarboxylase by 1-amino-oxy-3-aminopropane." Biochemical Journal 478, no. 23 (2021): 4137–49. http://dx.doi.org/10.1042/bcj20210647.

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Ornithine decarboxylase (ODC) is the rate-limiting enzyme for the synthesis of polyamines (PAs). PAs are oncometabolites that are required for proliferation, and pharmaceutical ODC inhibition is pursued for the treatment of hyperproliferative diseases, including cancer and infectious diseases. The most potent ODC inhibitor is 1-amino-oxy-3-aminopropane (APA). A previous crystal structure of an ODC–APA complex indicated that APA non-covalently binds ODC and its cofactor pyridoxal 5-phosphate (PLP) and functions by competing with the ODC substrate ornithine for binding to the catalytic site. We

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Kinoshita, T., A. W. Dodds, S. K. A. Law, and K. Inoue. "The low C5 convertase activity of the C4A6 allotype of human complement component C4." Biochemical Journal 261, no. 3 (1989): 743–48. http://dx.doi.org/10.1042/bj2610743.

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We have compared the C5-convertase-forming ability of different C4 allotypes, including the C4A6 allotype, which has low haemolytic activity and which has previously been shown to be defective in C5-convertase formation. Recent studies suggest that C4 plays two roles in the formation of the C5 convertase from the C3 convertase. Firstly, C4b acts as the binding site for C3 which, upon cleavage by C2, forms a covalent linkage with the C4b. Secondly, C4b with covalently attached C3b serves to form a high-affinity binding site for C5. Purified allotypes C4A3, C4B1 and C4A6 were used to compare the

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Ruddraraju, Kasi Viswanatharaju, and Zhong-Yin Zhang. "Covalent inhibition of protein tyrosine phosphatases." Molecular BioSystems 13, no. 7 (2017): 1257–79. http://dx.doi.org/10.1039/c7mb00151g.

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Lu, Jia-Hui, Zhen Li, Jia-Hui Chen, et al. "Adaptable Phosphate Networks towards Robust, Reprocessable, Weldable, and Alertable-Yet-Extinguishable Epoxy Vitrimer." Research 2022 (October 6, 2022): 1–12. http://dx.doi.org/10.34133/2022/9846940.

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Covalent adaptable networks (CANs) combine the uniqueness of thermoplastics and thermosets to allow for reprocessability while being covalently crosslinked. However, it is highly desirable but rarely achieved for CANs to simultaneously demonstrate reversibility and mechanical robustness. Herein, we report a feasible strategy to develop a novel epoxy vitrimer (EV) composed of adaptable phosphate networks (APNs), by which the EVs exhibit promising mechanical properties (tensile strength of 62.5 ~ 87.8 MPa and tensile modulus of 1360.1 ~ 2975.3 MPa) under ambient conditions. At elevated temperatu

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Sim, E., A. W. Dodds, and A. Goldin. "Inhibition of the covalent binding reaction of complement component C4 by penicillamine, an anti-rheumatic agent." Biochemical Journal 259, no. 2 (1989): 415–19. http://dx.doi.org/10.1042/bj2590415.

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D(-)-Penicillamine [D(-)-beta beta-dimethylcysteine] is an anti-arthritic drug, but its use is limited by adverse side effects, which include problems in immune-complex clearance. Complement is important as a source of inflammatory mediators in rheumatoid arthritis and is also involved in immune-complex clearance. Thus inhibition of the complement cascade would be likely to contribute to both the therapeutic and the toxic effects of penicillamine. It is shown that penicillamine and cysteine are potent inhibitors of the covalent binding of activated complement component C4 to immune complexes.

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Zhao, Yuguang, Fredrik Svensson, David Steadman, et al. "Structural Insights into Notum Covalent Inhibition." Journal of Medicinal Chemistry 64, no. 15 (2021): 11354–63. http://dx.doi.org/10.1021/acs.jmedchem.1c00701.

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Westover, Kenneth D., Pasi A. Jänne, and Nathanael S. Gray. "Progress on Covalent Inhibition of KRASG12C." Cancer Discovery 6, no. 3 (2016): 233–34. http://dx.doi.org/10.1158/2159-8290.cd-16-0092.

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Jacobs, Amy. "Covalent Inhibition of HIV Membrane Fusion." Biophysical Journal 96, no. 3 (2009): 359a. http://dx.doi.org/10.1016/j.bpj.2008.12.1814.

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Huang, Huang, Christina A. Howard, Sergei Zari, et al. "Covalent inhibition of NSD1 histone methyltransferase." Nature Chemical Biology 16, no. 12 (2020): 1403–10. http://dx.doi.org/10.1038/s41589-020-0626-6.

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Amara, Neri, Roi Mashiach, Dotan Amar, et al. "Covalent Inhibition of Bacterial Quorum Sensing." Journal of the American Chemical Society 131, no. 30 (2009): 10610–19. http://dx.doi.org/10.1021/ja903292v.

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NAGUMO, Yoko, Hideaki KAKEYA, Mitsuru SHOJI, Yujiro HAYASHI, Naoshi DOHMAE, and Hiroyuki OSADA. "Epolactaene binds human Hsp60 Cys442 resulting in the inhibition of chaperone activity." Biochemical Journal 387, no. 3 (2005): 835–40. http://dx.doi.org/10.1042/bj20041355.

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Epolactaene is a microbial metabolite isolated from Penicillium sp., from which we synthesized its derivative ETB (epolactaene tertiary butyl ester). In the present paper, we report on the identification of the binding proteins of epolactaene/ETB, and the results of our investigation into its inhibitory mechanism. Using biotin-labelled derivatives of epolactaene/ETB, human Hsp (heat-shock protein) 60 was identified as a binding protein of epolactaene/ETB in vitro as well as in situ. In addition, we found that Hsp60 pre-incubated with epolactaene/ETB lost its chaperone activity. The in vitro bi

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Kentner, Taryn A., Leslie R. Berry, and Anthony K. C. Chan. "Inhibition of Factor Xa in Prothrombinase Is Enhanced by Covalent Linkage of Antithrombin to Heparin." Blood 104, no. 11 (2004): 1051. http://dx.doi.org/10.1182/blood.v104.11.1051.1051.

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Abstract Prothrombinase is the surface-bound complex in which factor Xa (Xa) converts prothrombin to thrombin in vivo. Studies have shown that Xa within prothrombinase is resistant to inhibition by antithrombin + heparin (AT+H). Previously we found that, unlike AT+H, a covalent conjugate of AT and H (ATH) was able to neutralize fibrin-bound thrombin. In this study, AT+H and ATH were compared in their reaction with Xa in prothrombinase. Mixtures of CaCl2, PCPS vesicles, factor Va (Va) and prothrombin in TSP buffer were combined with either AT+H or ATH. Following addition of Xa, time samples wer

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Jebaraj, Billy Michael Chelliah, Annika Müller, Rashmi Priyadharshini Dheenadayalan, et al. "Evaluation of vecabrutinib as a model for noncovalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia." Blood 139, no. 6 (2022): 859–75. http://dx.doi.org/10.1182/blood.2021011516.

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Abstract Covalent Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib, have proven to be highly beneficial in the treatment of chronic lymphocytic leukemia (CLL). Interestingly, the off-target inhibition of IL-2-inducible T-cell kinase (ITK) by ibrutinib may also play a role in modulating the tumor microenvironment, potentially enhancing the treatment benefit. However, resistance to covalently binding BTK inhibitors can develop as the result of a mutation in cysteine 481 of BTK (C481S), which prevents irreversible binding of the drugs. In the present study we performed preclinical chara

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Thøgersen, I. B., G. Salvesen, F. H. Brucato, S. V. Pizzo та J. J. Enghild. "Purification and characterization of an α-macroglobulin proteinase inhibitor from the mollusc Octopus vulgaris". Biochemical Journal 285, № 2 (1992): 521–27. http://dx.doi.org/10.1042/bj2850521.

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The cell-free haemolymph of the mollusc Octopus vulgaris inhibited the proteolytic activity of the thermolysin against the high-molecular-mass substrate hide powder azure. The purified inhibitor was a glycoprotein composed of two identical 180 kDa disulphide-linked subunits. In addition to the inhibition of the metalloproteinase thermolysin, the protein inhibited the serine proteinases human neutrophil elastase, pig pancreatic elastase, bovine chymotrypsin, bovine trypsin and the cysteine proteinase papain. A fraction of the proteinase-inhibitor complex resisted dissociation after denaturation

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Wágner, Gábor, Tamara A. M. Mocking, Albert J. Kooistra, et al. "Covalent Inhibition of the Histamine H3 Receptor." Molecules 24, no. 24 (2019): 4541. http://dx.doi.org/10.3390/molecules24244541.

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Covalent binding of G protein-coupled receptors by small molecules is a useful approach for better understanding of the structure and function of these proteins. We designed, synthesized and characterized a series of 6 potential covalent ligands for the histamine H3 receptor (H3R). Starting from a 2-amino-pyrimidine scaffold, optimization of anchor moiety and warhead followed by fine-tuning of the required reactivity via scaffold hopping resulted in the isothiocyanate H3R ligand 44. It shows high reactivity toward glutathione combined with appropriate stability in water and reacts selectively

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Walderveen, Maria Christina Van, Leslie Roy Berry, Helen Mary Atkinson, and Anthony Kam Chuen Chan. "Covalent antithrombin-heparin effect on thrombin-thrombomodulin and activated protein C reaction with factor V/Va." Thrombosis and Haemostasis 103, no. 05 (2010): 910–19. http://dx.doi.org/10.1160/th09-07-0473.

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SummaryThrombomodulin (TM), which variably contains a chondroitin sulfate (±CS), forms an anticoagulant complex with thrombin (IIa). IIaTM(±CS) converts protein C (PC) into activated PC (APC), which then inactivates activated factors V (FVa) and VIII (FVIIIa). This reduces prothrombinase and tenase complexes that generate IIa. Heparin (H) increases the rate of IIa-TM inhibition by antithrombin (AT) and enhances FV cleavage by APC. Our novel covalent AT-H (ATH) product, has superior anticoagulant activity compared to AT + unfractionated H (UFH). We studied mechanisms by which ATH versus AT + UF

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Santiago Vispo, Nelson. "Covalent Peptide Evolution: Redefining Protein–Protein Interaction Inhibition Through Phage Display." Bionatura Journal 2, no. 2 (2025): 1–5. https://doi.org/10.70099/bj/2025.02.02.16.

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Covalent cyclic peptides represent a transformative approach for targeting challenging protein-protein interactions (PPIs) characterized by flat, extensive binding surfaces. Recent advances in electrophilic phage display now enable the evolution of these peptides through integrating sulfur(VI) fluoride exchange (SuFEx) chemistry with functional selection strategies. This innovative platform combines genetic encoding with site-specific cyclization and warhead incorporation to generate high-affinity, irreversible binders. When targeting the SARS-CoV-2 Spike-ACE2 interface, the approach produced

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Shatan, Anastasiia B., Vitalii Patsula, Hana Macková та ін. "Silver-Sulfamethazine-Conjugated β-Cyclodextrin/Dextran-Coated Magnetic Nanoparticles for Pathogen Inhibition". Nanomaterials 14, № 4 (2024): 371. http://dx.doi.org/10.3390/nano14040371.

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In the fight against antibiotic resistance, which is rising to dangerously high levels worldwide, new strategies based on antibiotic-conjugated biocompatible polymers bound to magnetic nanoparticles that allow the drug to be manipulated and delivered to a specific target are being proposed. Here, we report the direct surface engineering of nontoxic iron oxide nanoparticles (IONs) using biocompatible dextran (Dex) covalently linked to β-cyclodextrin (β-CD) with the ability to form non-covalent complexes with silver-sulfamethazine (SMT-Ag). To achieve a good interaction of β-CD-modified dextran

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Lee, Jesang, and Seung Bum Park. "Extended Applications of Small-Molecule Covalent Inhibitors toward Novel Therapeutic Targets." Pharmaceuticals 15, no. 12 (2022): 1478. http://dx.doi.org/10.3390/ph15121478.

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Recently, small-molecule covalent inhibitors have been accepted as a practical tool for targeting previously “undruggable” proteins. The high target selectivity of modern covalent inhibitors is now alleviating toxicity concerns regarding the covalent modifications of proteins. However, despite the tremendous clinical success of current covalent inhibitors, there are still unmet medical needs that covalent inhibitors have not yet addressed. This review categorized representative covalent inhibitors based on their mechanism of covalent inhibition: conventional covalent inhibitors, targeted coval

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Stevic, Ivan, Howard H. W. Chan, Ankush Chander, Leslie R. Berry, and Anthony K. C. Chan. "Inhibition of Platelet-Prothrombianse by a Covalent Antithrombin-Heparin Complex." Blood 120, no. 21 (2012): 2212. http://dx.doi.org/10.1182/blood.v120.21.2212.2212.

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Abstract Abstract 2212 Introduction: Factor Xa is protected within the prothrombinase complex from inhibition by heparin. We have developed a covalent antithrombin-heparin complex (ATH) with enhanced anticoagulant activity. Previously, we have shown that ATH is able to inhibit coagulation enzymes much more efficiently than regular antithrombin+heparin (AT+UFH). For example, ATH inhibited TF/VIIa ∼30-fold faster compared to AT+UFH. Furthermore, we have also demonstrated that ATH is capable of inhibiting Xa within a prothrombinase complex assembled on synthetic phospholipid vesicles better than

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Zhou, Yuxin, Ji Tao, Dingshuainan Jin, Shiping Zhang, Yan He, and Longlong Niu. "The Inhibition Effect and Mechnism of a Thiadiazole Derivative on Q235 Carbon Steel in 1 M HCl Solution." Applied Sciences 13, no. 4 (2023): 2103. http://dx.doi.org/10.3390/app13042103.

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N,N-dihydroxyethyl-(5-methyl-[1,3,4] thiadiazol-2-sulfur)-carbonyl acetamide was synthesized and used as an inhibitor to protect Q235 carbon steel in a 1 M HCl solution. The results showed an increased inhibition efficiency with the increase in the concentration of this inhibitor, and an inhibition efficiency higher than 96% at 40 mg/L can be obtained from weight loss, electrochemical impedance spectroscopy, and potentiodynamic polarization results. The inhibition effect was determined by the adsorption film according to the surface morphology and elemental distribution of the carbon steel sur

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Allgardsson, Anders, Lotta Berg, Christine Akfur, et al. "Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6." Proceedings of the National Academy of Sciences 113, no. 20 (2016): 5514–19. http://dx.doi.org/10.1073/pnas.1523362113.

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Organophosphorus nerve agents interfere with cholinergic signaling by covalently binding to the active site of the enzyme acetylcholinesterase (AChE). This inhibition causes an accumulation of the neurotransmitter acetylcholine, potentially leading to overstimulation of the nervous system and death. Current treatments include the use of antidotes that promote the release of functional AChE by an unknown reactivation mechanism. We have used diffusion trap cryocrystallography and density functional theory (DFT) calculations to determine and analyze prereaction conformers of the nerve agent antid

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Lee, Chang-Uk, and Tom N. Grossmann. "Reversible Covalent Inhibition of a Protein Target." Angewandte Chemie International Edition 51, no. 35 (2012): 8699–700. http://dx.doi.org/10.1002/anie.201203341.

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