Journal articles: 'Discontinuous epitope'

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Tran, Vinh Ngoc, Quy Cam Vo, and Thuoc Linh Tran. "PREDICTION OF B-CELL DISCONTINUOUS EPITOPES ON MATRIX PROTEIN OF H5N1 VIRUS." Science and Technology Development Journal 12, no. 9 (May 15, 2009): 31–37. http://dx.doi.org/10.32508/stdj.v12i9.2283.

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Although discontinuous epitopes make up 90% of total number of B-cell epitopes, however, because of difficulties in the development of method for their prediction, most of the B-cell epitope prediction methods today focus on continuous epitopes. To serve for the development of vaccine against H5N1 virus, we have been studying on in silico prediction of T- and B-cell continuous as well as B-cell discontinuous epitopes on H5N1 viral antigens. In this study, using the homology modeling method, we have generated structures of matrix protein of the H5N1 virus and predicted B-cell discontinuous epitopes. 60 out of 72 predicted residues were similar with those reported by the CEP method (Conformational Epitope Prediction). All predicted aminoacid residues were hydrophilic, polar, electrically charged and located on the surface of the antigen structures.

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Lebreton, Aurélien, Noémie Simon, Violaine Moreau, Vincent Demolombe, Christopher Cayzac, Christophe Nguyen, Priscilla Lapalud, et al. "Discontinuous Epitopes On FVIII A2 Domain Mapped by Computer-Designed Synthetic Peptides." Blood 120, no. 21 (November 16, 2012): 1120. http://dx.doi.org/10.1182/blood.v120.21.1120.1120.

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Abstract Abstract 1120 Context: The development of alloantibodies (AlloAbs) directed against the factor VIII (FVIII) is actually the main iatrogenic complication in hemophilia A (HA). Immune tolerance induction (ITI) is the only validated treatment to eradicate inhibitors. ITI is based on the infusion of high doses of therapeutic FVIII. It has been recently suggested that epitope specificity during ITI could be related to the outcome of this therapy. Anti-FVIII immune response is polyclonal, complex, dynamic over time and preferentially directed against C2 and A2 domains of FVIII. Tools for fine epitope mapping are useful to identify new epitopes and follow the over time evolution of epitope specificity. The aim of our work was to identify new epitopes on FVIII A2 domain using computer-designed peptides mimicking discontinuous epitopes. We used a multiplex assay based on Luminex™ technology to select the most reactive peptide (1). Patients and methods: All the peptides were predicted by a bioinformatical tool named PEPOP using a new protocol of prediction. Starting from the tridimensional structure of the FVIII, PEPOP were able to work out the sequence of 40 peptides mimicking discontinuous epitopes distributed on the A2 domain surface. Seven negative control peptides were predicted in unaccessible solvant area. A previously published peptide mimicking a linear epitope (residues 484–508) were also synthetized and tested (2). The capacity of peptides to block the binding of the anti-A2 inhibitors on beads coated with the A2 domain obtained by thrombin cleavage of FVIII was assessed. This multiplexed inhibition assay were based on Luminex™ technology. We used a pool of 10 plasma with anti-A2 domain inhibitors as a source of antibodies. Results: The inhibition assays realized with pool of anti-A2 antibodies made it possible to identify 2 peptides mimicking discontinuous epitopes on the A2 domain. The inhibition rate of the two new identified peptides reaches to 50% and 26% at the maximal concentration. We also confirm that the previously published peptide is able to block the binding of anti-A2 inhibitors in our population. The localization of the discontinuous epitopes mimicked by peptides within the tridimensional structure of the A2 domain showed than these epitopes are only represented on a restricted area. Conclusion: We identified two peptides mimicking new discontinuous epitopes on the A2 domain and predicted by a new algorithm of PEPOP. According to the literature, immune response against A2 domain seems to be more restricted. Several residues involved in the new identified discontinuous epitopes are crucial for thrombin, protein S, FIXa and low-density lipoprotein receptor-related protein (LRP) interactions. Tools for fine epitope mapping are essential to identify epitopes on FVIII domains, with a particular concern for discontinuous epitopes. Further studies are needed to validate the concept that fine epitope mapping at the epitope level could be useful to predict ITI outcome. Disclosures: No relevant conflicts of interest to declare.

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Tran, Kim Thi Hong, and Thuoc Linh Tran. "Synthesis and immunogenicity evaluating of a discontinuous B-cell epitope predicted from influenza virus A/H5N1 HA antigen." Science and Technology Development Journal 18, no. 2 (June 30, 2015): 59–69. http://dx.doi.org/10.32508/stdj.v18i2.1134.

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To develop vaccine with stable efficiency against easily transforming virus such as influenza A/H5N1 virus, bioinformatic tools have been used to predict conserved epitopes from viral antigens to be used as materials for the development of polyvalent vaccine against this virus. Using this approach, we have successfully predicted one discontinuous B-cell epitope, a peptide of 14 aminoacids on conserved domains of HA antigen from H5N1 influenza A virus. In this study, we report results of the preparation of this discontinuous B-cell epitope as the recombinant fusion form with H:1,2 flagellin from Salmonella typhimurium to increase the immunogenicity of this epitope using genetic manipulating techniques with Escherichia coli as host cell. The immunogenicity of the chemically synthesized predicted epitope and the recombinant epitope was examined by immunization of each of these epitopes to mice. Using hemagglutination inhibition (HI) method, we successfully demonstrated that both anti-sera from mice immunized either with chemically synthesized peptide or with recombinant flagellin H:1,2 fused epitope could recognize and inhibit the agglutination of inactivated influenza H5N1 virus strains, such as A/H5N1/ Chicken13/ Vietnam/LA/2006 and A/Vietnam/CL26/2004 (H5N1) isolated from infected chicken and human in Vietnam.

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Setiawan, Tirta, and Rizarullah Rizarullah. "Predicting Multi-Epitope Peptide Cancer Vaccine from Novel TAA Topo48." Journal of Science and Applicative Technology 5, no. 1 (May 7, 2021): 171. http://dx.doi.org/10.35472/jsat.v5i1.349.

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Cancer is one of the most lethal diseases. Recently, cancer immunotherapy has a tremendous achievement in cancer treatment. A certain number of cancer based epitope vaccines with different moiety have been discovered. In japan, several clinical tests of cancer based epitope vaccine derived from tumor associated antigens (TAAs) are now ongoing or have recently been completed. a novel of TAAs potentially as cancer vaccine have been retrieved from a fragment weighed 48kDa derived from human DNA-topoisomerase 1 (TOP1) called Topo48. Therefore, it is still critical to discover a derived Topo48 epitope based cancer vaccine. Immuno-informatics considered as a methods noted to have better accuracy to design promising vaccine candidates. Here, continuous and discontinuous B-cell epitopes following with CTL epitopes and their docking interaction to major histocompatibility complex (MHC) class I Human Leukocyte Antigens (HLA)- A0201 were predicted. Kolaskar-Tongaonkar’s, Emini’s, Karpus-Schulz’s, and Parker’s methods were used to predict continuous B-cell epitopes while ElliPro was used for prediction of discontinued B-cell epitopes. Those considered methods marked to have better accuracy to design promising vaccine candidates. Similarly, CTL epitopes was also predicted by using NetCTL server and the best candidates were further investigated their binding affinity by mean of PEP-FOLD3, PatchDock rigid-body docking server, and FireDock server. Total 27 continuous epitopes and 7 discontinuous B-cell epitopes were predicted. In the other hand, 9 peptides were predicted as CTL epitopes. Whereas, three predicted CTL epitope in range 263MLDHEYTTK27, 755AIDMADEDY763, 715ALGTSKLNY724) exhibited good interactions to HLA-A0201. Moreover, we also found residues His266, Thr270, Ala755, Tyr723, Thr718, Ser719, Lys720 from Topo48 and residues Thr163, Asp757, His70, Glu63 from HLA- A0201 were indicated to be antigenic. Ultimately, our proposed continuous/discontinuous B-cell epitopes, and also CTL epitopes can be potential vaccines for cancer immunotherapy.

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Charrel-Dennis, M., AM Jackson, T. Lund, AJ Lapthorn, P. Berger, IM Roitt, and PJ Delves. "The major hormone-specific discontinuous epitopes on human chorionic gonadotrophin." Journal of Molecular Endocrinology 32, no. 2 (April 1, 2004): 571–81. http://dx.doi.org/10.1677/jme.0.0320571.

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The hormone human chorionic gonadotrophin (hCG) shows extensive sequence homology with LH. Thus, many of the antigenic epitopes on hCG are shared with LH, leading to immunological cross-reaction between these two hormones. Anti-fertility and anti-cancer vaccines based upon hCG should ideally target only the hCG-specific epitopes. The hCG-unique linear epitopes located in the C-terminal peptide of the hCG beta-chain are well characterised. In contrast, the hCG-specific discontinuous epitopes, termed beta1, beta6 and beta7, have remained poorly defined. By generating hCG beta-chain molecules containing single amino acid substitutions we have identified R10, N13, R60 and Q89 as being important in the formation of the beta1 epitope, with R60 providing a particularly dominant residue. We also show that the amino acid residue Q89 contributes to the beta7 epitope, whilst D61 plays a role in both the beta6 and beta7 epitopes.

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Etemad-Moghadam, Bijan, Gunilla B. Karlsson, Matilda Halloran, Ying Sun, Dominik Schenten, Mark Fernandes, Norman L. Letvin, and Joseph Sodroski. "Characterization of Simian-Human Immunodeficiency Virus Envelope Glycoprotein Epitopes Recognized by Neutralizing Antibodies from Infected Monkeys." Journal of Virology 72, no. 10 (October 1, 1998): 8437–45. http://dx.doi.org/10.1128/jvi.72.10.8437-8445.1998.

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ABSTRACT We characterized human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein epitopes recognized by neutralizing antibodies from monkeys recently infected by molecularly cloned simian-human immunodeficiency virus (SHIV) variants. The early neutralizing antibody response in each infected animal was directed mainly against a single epitope. This primary neutralizing epitope, however, differed among individual monkeys infected by identical viruses. Two such neutralization epitopes were determined by sequences in the V2 and V3 loops of the gp120 envelope glycoprotein, while a third neutralization epitope, apparently discontinuous, was determined by both V2 and V3 sequences. These results indicate that the early neutralizing antibody response in SHIV-infected monkeys is monospecific and directed against epitopes composed of the gp120 V2 and V3 variable loops.

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Mitran, Catherine J., Lauren M. Higa, Michael F. Good, and Stephanie K. Yanow. "Generation of a Peptide Vaccine Candidate against Falciparum Placental Malaria Based on a Discontinuous Epitope." Vaccines 8, no. 3 (July 18, 2020): 392. http://dx.doi.org/10.3390/vaccines8030392.

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In pregnant women, Plasmodium falciparum-infected red blood cells adhere to the placenta via the parasite protein VAR2CSA. Two vaccine candidates based on VAR2CSA are currently in clinical trials; however, these candidates failed to elicit strain-transcending antibody responses. We previously showed that a cross-reactive monoclonal antibody (3D10) raised against the P. vivax antigen PvDBP targets epitopes in VAR2CSA. We now aim to design a peptide vaccine against VAR2CSA based on the epitope that generated 3D10. We mapped the epitope to subdomain 1 (SD1) of PvDBP and identified a peptide that contained the minimal sequence. However, this peptide did not elicit cross-reactive VAR2CSA antibodies in mice. When tested against a broader, overlapping peptide array spanning SD1, 3D10 in fact recognized a discontinuous epitope consisting of three segments of SD1. These findings presented the challenge to generate this larger structural epitope as a synthetic peptide since it is stabilized by two pairs of disulfide bonds. We overcame this using a synthetic scaffold to conformationally constrain the SD1 peptide and coupled it to keyhole limpet hemocyanin (KLH). The SD1-KLH conjugate elicited antibodies in mice that cross-reacted with VAR2CSA. This strategy successfully recapitulated a discontinuous epitope with a synthetic peptide and represents the first heterologous vaccine candidate against VAR2CSA.

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Moreau, V., C. Granier, S. Villard, D. Laune, and F. Molina. "Discontinuous epitope prediction based on mimotope analysis." Bioinformatics 22, no. 9 (January 24, 2006): 1088–95. http://dx.doi.org/10.1093/bioinformatics/btl012.

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Conway, J. F., N. R. Watts, D. M. Belnap, N. Cheng, S. J. Stahl, P. T. Wingfield, and A. C. Steven. "Characterization of a Conformational Epitope on Hepatitis B Virus Core Antigen and Quasiequivalent Variations in Antibody Binding." Journal of Virology 77, no. 11 (June 1, 2003): 6466–73. http://dx.doi.org/10.1128/jvi.77.11.6466-6473.2003.

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ABSTRACT We have characterized a conformational epitope on capsids of hepatitis B virus (HBV) by cryo-electron microscopy and three-dimensional image reconstruction of Fab-labeled capsids to ∼10-Å resolution, combined with molecular modeling. The epitope straddles the interface between two adjacent subunits and is discontinuous, consisting of five peptides—two on one subunit and three on its neighbor. Together, the two icosahedral forms of the HBV capsid—T=3 and T=4 particles—present seven quasiequivalent variants of the epitope. Of these, only three bind this Fab. Occupancy ranges from ∼100 to ∼0%, reflecting conformational variations in the epitope and steric blocking effects. In the former, small shifts of the component peptides have large effects on binding affinity. This approach appears to hold general promise for elucidating conformational epitopes of HBV and other viruses, including those of neutralizing and diagnostic significance.

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White, John R., Victoria Boyd, Gary S. Crameri, Christine J. Duch, Ryan K. van Laar, Lin-Fa Wang, and Bryan T. Eaton. "Location of, immunogenicity of and relationships between neutralization epitopes on the attachment protein (G) of Hendra virus." Journal of General Virology 86, no. 10 (October 1, 2005): 2839–48. http://dx.doi.org/10.1099/vir.0.81218-0.

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Epitopes involved in a protective immune response to Hendra virus (HeV) (Henipavirus, Paramxyoviridae) were investigated by generating five neutralizing monoclonal antibodies (mAbs) to the virus attachment protein (G) of HeV (HeV G) and sequencing of the G gene of groups of neutralization-escape variants selected with each mAb. Amino acid substitutions occurred at eight distinct sites on HeV G. Relationships between these sites were investigated in binding and neutralization assays using heterologous combinations of variants and mAbs. The sites were also mapped to a proposed structural model for the attachment proteins of Paramyxoviridae. Their specific locations and the nature of their interactions with the mAb panel provided the first functional evidence that HeV G in fact resembled the proposed structure. Four sites (aa 183–185, 417, 447 and 570) contributed to a major discontinuous epitope, on the base of the globular head, that was similar to immunodominant virus neutralization sites found in other paramyxoviruses. Amino acid similarity between HeV and Nipah virus was relatively highly conserved at these sites but decreased significantly at the other sites identified in this study. These included another discontinuous epitope on the base of the head region defined by sites aa 289 and 324 and well separated epitopes on the top of the head at sites aa 191–195 and 385–356. The latter epitope corresponded to immunodominant neutralization sites found in Rinderpest virus and Measles virus.

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Linke, Michael J., Susan M. Sunkin, Ryan P. Andrews, James R. Stringer, and Peter D. Walzer. "Expression, Structure, and Location of Epitopes of the Major Surface Glycoprotein of Pneumocystis carinii f. sp. carinii." Clinical Diagnostic Laboratory Immunology 5, no. 1 (January 1, 1998): 50–57. http://dx.doi.org/10.1128/cdli.5.1.50-57.1998.

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ABSTRACT The major surface glycoprotein (MSG) of Pneumocystis carinii f. sp. carinii consists of a heterogeneous family of proteins that are encoded by approximately 100 unique genes. A genomic expression library was screened with a panel of MSG-specific monoclonal antibodies (MAbs) to identify conserved and rare epitopes. All of the antibodies reacted with epitopes that are encoded within the 5′ end of MSG. The results from the expression screening identified antibodies that recognize highly conserved, moderately conserved, and rare epitopes. Four MAbs (MAbs RA-F1, RA-E7, RA-G10, and RB-E3) reacted with a maltose binding protein–MSG-B fusion protein (MBPMSG-B41–1065) by immunoblotting and enzyme-linked immunosorbent assay. Three of the MAbs (MAbs RA-F1, RA-G10, and RA-E7) reacted with the same continuous epitope that was localized to amino acids 278 to 290 of MSG-B. Comparison of the sequence of the RA-F1-, RA-G10-, and RA-E7-reactive epitope to the deduced amino acid sequences of multiple MSGs demonstrated that it is highly conserved. The reactivity of RB-E3 with MSG-B was shown to be dependent on amino acids 184 to 192, which may comprise a portion of a discontinuous epitope.

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Russell, Bonnie L., Nishal Parbhoo, and Samantha Gildenhuys. "Analysis of Conserved, Computationally Predicted Epitope Regions for VP5 and VP7 Across three Orbiviruses." Bioinformatics and Biology Insights 12 (January 1, 2018): 117793221875534. http://dx.doi.org/10.1177/1177932218755348.

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Orbiviruses are double-stranded RNA viruses that have profound economic and veterinary significance, 3 of the most important being African horse sickness virus (AHSV), bluetongue virus (BTV), and epizootic hemorrhagic disease virus (EHDV). Currently, vaccination and vector control are used as preventative measures; however, there are several problems with the current vaccines. Comparing viral amino acid sequences, we obtained an AHSV-BTV-EHDV consensus sequence for VP5 (viral protein 5) and for VP7 (viral protein 7) and generated homology models for these proteins. The structures and sequences were analyzed for amino acid sequence conservation, entropy, surface accessibility, and epitope propensity, to computationally determine whether consensus sequences still possess potential epitope regions. In total, 5 potential linear epitope regions on VP5 and 11 on VP7, as well as potential discontinuous B-cell epitopes, were identified and mapped onto the homology models created. Regions identified for VP5 and VP7 could be important in vaccine design against orbiviruses.

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Wiens, Gregory D., and Jennifer Owen. "Mapping of Neutralizing Epitopes on Renibacterium salmoninarum p57 by Use of Transposon Mutagenesis and Synthetic Peptides." Applied and Environmental Microbiology 71, no. 6 (June 2005): 2894–901. http://dx.doi.org/10.1128/aem.71.6.2894-2901.2005.

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ABSTRACT Renibacterium salmoninarum is a gram-positive bacterium that causes bacterial kidney disease in salmonid fish. The virulence mechanisms of R. salmoninarum are not well understood. Production of a 57-kDa protein (p57) has been associated with isolate virulence and is a diagnostic marker for R. salmoninarum infection. Biological activities of p57 include binding to eukaryotic cells and immunosuppression. We previously isolated three monoclonal antibodies (4D3, 4C11, and 4H8) that neutralize p57 activity. These monoclonal antibodies (MAbs) bind to the amino-terminal region of p57 between amino acids 32 though 243; however, the precise locations of the neutralizing epitopes were not determined. Here, we use transposon mutagenesis to map the 4D3, 4C11, and 4H8 epitopes. Forty-five transposon mutants were generated and overexpressed in Escherichia coli BL21(DE3). The ability of MAbs 4D3, 4H8, and 4C11 to bind each mutant protein was assessed by immunoblotting. Transposons inserting between amino acids 51 and 112 disrupted the 4H8 epitope. Insertions between residues 78 and 210 disrupted the 4C11 epitope, while insertions between amino acids 158 and 234 disrupted the 4D3 epitope. The three MAbs failed to bind overlapping, 15-mer peptides spanning these regions, suggesting that the epitopes are discontinuous in conformation. We conclude that recognition of secondary structure on the amino terminus of p57 is important for neutralization. The epitope mapping studies suggest directions for improvement of MAb-based immunoassays for detection of R. salmoninarum-infected fish.

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Gadkari, R. A., S. Roy, N. Rekha, N. Srinivasan, and R. R. Dighe. "Identification of a heterodimer-specific epitope present in human chorionic gonadotrophin (hCG) using a monoclonal antibody that can distinguish between hCG and human LH." Journal of Molecular Endocrinology 34, no. 3 (June 2005): 879–87. http://dx.doi.org/10.1677/jme.1.01683.

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Human chorionic gonadotrophin (hCG) is secreted during early pregnancy and is required for implantation and maintenance of the pregnancy. Active or passive immunoneutralization of hCG results in termination of pregnancy and this forms the basis of the hCG-based female contraceptive vaccine. However, the β subunit of hCG possesses 85% sequence homology with the first 114 amino acids of the β subunit of pituitary human LH (hLH), which is required for ovulation and maintenance of the corpus luteum function during the menstrual cycle. Immunization against hCG or its β subunit leads to generation of antibodies that can neutralize hLH due to many shared epitopes and hence may cause abnormal menstrual cycles. Therefore, it is essential to identify epitopes that are different in the two hormones. In the present study, we report a monoclonal antibody (MAb) specific for hCG that shows no binding to the isolated subunits. Interestingly, the MAb also does not bind hLH at all. The epitope mapping analysis revealed that this antibody recognizes a unique discontinuous epitope present only in the heterodimeric hCG and is distinct from the unique C-terminal extension of hCGβ that is absent in hLHβ. The MAb, either as IgG or its recombinant single-chain variable region fragment, inhibited the response to hCG, but not to hLH. Thus, the epitope recognized by this MAb is an ideal candidate antigen for immunocontraception.

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Munera, Marlon, Neyder Contreras, Andres Sánchez, Jorge Sánchez, and Yuliana Emiliani. "In silico analysis of a major allergen from Rattus norvegicus, Rat n 1, and cross-reactivity with domestic pets." F1000Research 8 (October 1, 2019): 1707. http://dx.doi.org/10.12688/f1000research.20534.1.

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Background: Lipocalins play a role in the cellular trafficking of pheromones and are involved in allergic responses to domestic pets. However, the cross-reactivity among allergens of this group has been poorly explored, and the pheromone linking capacity is not well characterized. The aim of this study was to explore cross-reactive epitopes and pheromone linking capacity among Rat n 1 and homologues in domestic pets through an in silico approach. Methods: ElliPro and BepiPred in silico tools were used to predict B cell linear and cross-reactive epitopes. The pheromone linking capacity was explored by docking virtual screening with 2-ethylhexanol, 2,5-dimethylpyrazine, 2-sec-butyl-4,5-dihydrothiazole, and 2-heptanone ligands. Results: According to the analysis, Rat n 1 shares 52% identity with Equ c 1, Can f 6, Fel d 4, and Mus m 1 allergens. The overlapping structures assay revealed high structural homology (root mean square deviation < 1). Four lineal and three discontinuous epitopes were predicted on Ra t n 1. A lineal epitope located between amino acids residues 24 and 36 was highly conserved on all allergens explored. A cross-reactive discontinuous epitope (T142, K143, D144, L145, S146, S147, D148, K152, L170, T171, T173, D174) was also found. Docking molecular simulations revealed the active site, and we identified the properties of the binding of four pheromones and the binding potential of Rat n 1. Critical residues for interactions are reported in this study. Conclusions: We identified some possible allergens from Rattus norvegicus, and those allergens could have cross-reactivity with allergens from some animals. The results need to be confirmed with in vitro studies and could be utilized to contribute to immunotherapy and reduce allergic diseases related to lipocalins.

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Munera, Marlon, Neyder Contreras, Andres Sánchez, Jorge Sánchez, and Yuliana Emiliani. "In silico analysis of a major allergen from Rattus norvegicus, Rat n 1, and cross-reactivity with domestic pets." F1000Research 8 (December 12, 2019): 1707. http://dx.doi.org/10.12688/f1000research.20534.2.

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Background: Lipocalins play a role in the cellular trafficking of pheromones and are involved in allergic responses to domestic pets. However, the cross-reactivity among allergens of this group has been poorly explored, and the pheromone linking capacity is not well characterized. The aim of this study was to explore cross-reactive epitopes and pheromone linking capacity among Rat n 1 and homologues in domestic pets through an in silico approach. Methods: ElliPro and BepiPred in silico tools were used to predict B cell linear and cross-reactive epitopes. The pheromone linking capacity was explored by docking virtual screening with 2-ethylhexanol, 2,5-dimethylpyrazine, 2-sec-butyl-4,5-dihydrothiazole, and 2-heptanone ligands. Results: According to the analysis, Rat n 1 shares 52% identity with Equ c 1, Can f 6, Fel d 4, and Mus m 1 allergens. The overlapping structures analysis revealed high structural homology (root mean square deviation < 1). Four lineal and three discontinuous epitopes were predicted on Ra t n 1. A lineal epitope located between amino acids residues 24 and 36 was highly conserved on all allergens explored. A cross-reactive discontinuous epitope (T142, K143, D144, L145, S146, S147, D148, K152, L170, T171, T173, D174) was also found. Docking molecular simulations revealed the region involved in linking ligands, and we identified the properties of the binding of four pheromones and the binding potential of Rat n 1. Critical residues for interactions are reported in this study. Conclusions: We identified some possible allergens from Rattus norvegicus, and those allergens could have cross-reactivity with allergens from some animals. The results need to be confirmed with in vitro studies and could be utilized to contribute to immunotherapy and reduce allergic diseases related to lipocalins.

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Rudometov, Andrey P., Anton N. Chikaev, Nadezhda B. Rudometova, Denis V. Antonets, Alexander A. Lomzov, Olga N. Kaplina, Alexander A. Ilyichev, and Larisa I. Karpenko. "Artificial Anti-HIV-1 Immunogen Comprising Epitopes of Broadly Neutralizing Antibodies 2F5, 10E8, and a Peptide Mimic of VRC01 Discontinuous Epitope." Vaccines 7, no. 3 (August 6, 2019): 83. http://dx.doi.org/10.3390/vaccines7030083.

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The construction of artificial proteins using conservative B-cell and T-cell epitopes is believed to be a promising approach for a vaccine design against diverse viral infections. This article describes the development of an artificial HIV-1 immunogen using a polyepitope immunogen design strategy. We developed a recombinant protein, referred to as nTBI, that contains epitopes recognized by broadly neutralizing HIV-1 antibodies (bNAbs) combined with Th-epitopes. This is a modified version of a previously designed artificial protein, TBI (T- and B-cell epitopes containing Immunogen), carrying four T- and five B-cell epitopes from HIV-1 Env and Gag proteins. To engineer the nTBI molecule, three B-cell epitopes of the TBI protein were replaced with the epitopes recognized by broadly neutralizing HIV-1 antibodies 10E8, 2F5, and a linear peptide mimic of VRC01 epitope. We showed that immunization of rabbits with the nTBI protein elicited antibodies that recognize HIV-1 proteins and were able to neutralize Env-pseudotyped SF162.LS HIV-1 strain (tier 1). Competition assay revealed that immunization of rabbits with nTBI induced mainly 10E8-like antibodies. Our findings support the use of nTBI protein as an immunogen with predefined favorable antigenic properties.

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Binder, Mascha, Florian Otto, Roland Mertelsmann, Hendrik Veelken, and Martin Trepel. "The epitope recognized by rituximab." Blood 108, no. 6 (September 15, 2006): 1975–78. http://dx.doi.org/10.1182/blood-2006-04-014639.

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AbstractRituximab is a monoclonal antibody widely used in the treatment of malignant lymphoma and autoimmunity. Its epitope within the B-cell antigen CD20 is largely unknown. We used phage display libraries to select peptides binding to rituximab. Enriched peptides showed 2 sequence patterns: one motif (CALMIANSC) is related to (170)ANPS(173) within CD20, while another motif (WEWTI) may mimic the CD20 segment (182)YCYSI(185). Phages displaying either motif specifically bound rituximab. Binding to rituximab by the CD20 peptides ANPS and YCYSI was weak when used separately and enhanced when both peptides were linked. Recombinant CD20 extracellular loop proteins blocked binding of the selected CWWEWTIGC phage to rituximab, suggesting that CWWEWTIGC mimics the epitope. Blocking capacity was strongly reduced upon mutation of the CD20 strings ANPS or YCYSI. We conclude that rituximab binds a discontinuous epitope in CD20, comprised of (170)ANPS(173) and (182)YCYSI(185), with both strings brought in steric proximity by a disulfide bridge between C(167) and C(183).

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Enayat, M. S., F. G. H. Hill, W. Robinson, C. V. Prowse, and V. S. Hornsey. "Evaluation of Monoclonal Antibodies to vWf Antigen for Use in Autoradiographing vWf Multimer Analysis." Thrombosis and Haemostasis 57, no. 02 (1987): 217–21. http://dx.doi.org/10.1055/s-0038-1651097.

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SummaryNine monoclonal antibodies (MAb, coded ESvWF 1-5, 7-10) to human von Willebrand’s factor (vWf) have been studied for their labelling characteristics with 125I and their ability to demonstrate vWf multimers by autoradiography after discontinuous SDS electrophoresis on agarose and agarose/acrylamide gels in plasma from normal and von Willebrand’s disease (vWD) patients. Of ESvWF 1, 2, 4, 7, 8 and 9, ESvWF 2 gave autoradiographs most similar to those obtained with a polyclonal antibody. The others gave much fainter staining of all bands suggesting that the epitope detected by ESvWF 2 is either more common or, less easily altered by SDS than the epitopes identified by the other MAb’s. ESvWF 2 gave a different staining pattern with a IIC vWD patient than that obtained using a polyclonal antibody. The most striking result, however, was shown by ESvWF 3, 5 and 10 which failed to stain the lower band of the lower molecular weight multimer. This suggests that the lower triplet band, unlike the central and upper bands of the triplet, does not contain the epitope identified by these three MAb’s. With these reagents it has been possible to show, for the first time, that epitope differences do exist between the constituent bands of the vWf triplet.

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Sattentau, Q. J., J. Arthos, K. Deen, N. Hanna, D. Healey, P. C. Beverley, R. Sweet, and A. Truneh. "Structural analysis of the human immunodeficiency virus-binding domain of CD4. Epitope mapping with site-directed mutants and anti-idiotypes." Journal of Experimental Medicine 170, no. 4 (October 1, 1989): 1319–34. http://dx.doi.org/10.1084/jem.170.4.1319.

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The CD4 molecule, a differentiation marker expressed primarily by T lymphocytes, plays an important role in lymphocyte activation. CD4 is also the receptor for HIV. A number of recent studies have localized the high affinity binding site of the HIV envelope glycoprotein, gp120, to the NH2-terminal (V1) domain of CD4, a region with sequence and predicted structural homology with Ig kappa chain V domains (V kappa). In this report, we show that V1 bears structural similarities with V kappa regions through detailed epitope mapping of 26 CD4 mAbs. The binding sites of these mAbs were initially defined relative to one another by crossblocking analysis and were then localized to specific domains of CD4 in blocking studies with truncated, soluble CD4 proteins. The epitopes within the V1 domain were mapped in detail with a panel of 17 substitution mutants, and the specificities of several mAbs that appear to recognize very similar epitopes were examined in crossblocking studies with anti-idiotype antibodies. The location of the epitopes is consistent with a V kappa-like structure of V1. Most of the epitopes lie within regions of predicted exposed loops. A number of these epitopes span discontinuous residues in the linear sequence that lies in close proximity in an Ig fold. Alignment of CD4 V1 with the Ig V kappa chains places these epitopes within stretches corresponding to the complimentarity-determining regions. This epitope analysis is relevant for a vaccine strategy for HIV based on anti-idiotype antibodies to CD4 mAbs and for studies with CD4 antibodies on the role of CD4 in T lymphocyte activation.

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Wang, Dongliang, Jinhui Mai, Wenfeng Zhou, Wanting Yu, Yang Zhan, Naidong Wang, Neal D. Epstein, and Yi Yang. "Immunoinformatic Analysis of T- and B-Cell Epitopes for SARS-CoV-2 Vaccine Design." Vaccines 8, no. 3 (July 3, 2020): 355. http://dx.doi.org/10.3390/vaccines8030355.

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Currently, there is limited knowledge about the immunological profiles of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We used computer-based immunoinformatic analysis and the newly resolved 3-dimensional (3D) structures of the SARS-CoV-2 S trimeric protein, together with analyses of the immunogenic profiles of SARS-CoV, to anticipate potential B-cell and T-cell epitopes of the SARS-CoV-2 S protein for vaccine design, particularly for peptide-driven vaccine design and serological diagnosis. Nine conserved linear B-cell epitopes and multiple discontinuous B-cell epitopes composed of 69 residues on the surface of the SARS-CoV-2 trimeric S protein were predicted to be highly antigenic. We found that the SARS-CoV-2 S protein has a different antigenic profile than that of the SARS-CoV S protein due to the variations in their primary and 3D structures. Importantly, SARS-CoV-2 may exploit an immune evasion mechanism through two point mutations in the critical and conserved linear neutralization epitope (overlap with fusion peptide) around a sparsely glycosylated area. These mutations lead to a significant decrease in the antigenicity of this epitope in the SARS-CoV-2 S protein. In addition, 62 T-cell epitopes in the SARS-CoV-2 S protein were predicted in our study. The structure-based immunoinformatic analysis for the SARS-CoV-2 S protein in this study may improve vaccine design, diagnosis, and immunotherapy against the pandemic of COVID-19.

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Williamson, R. Anthony, David Peretz, Clemencia Pinilla, Hadyn Ball, Raiza B. Bastidas, Roman Rozenshteyn, Richard A. Houghten, Stanley B. Prusiner, and Dennis R. Burton. "Mapping the Prion Protein Using Recombinant Antibodies." Journal of Virology 72, no. 11 (November 1, 1998): 9413–18. http://dx.doi.org/10.1128/jvi.72.11.9413-9418.1998.

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ABSTRACT The fundamental event in prion disease is thought to be the posttranslational conversion of the cellular prion protein (PrPC) into a pathogenic isoform (PrPSc). The occurrence of PrPC on the cell surface and PrPSc in amyloid plaques in situ or in aggregates following purification complicates the study of the molecular events that underlie the disease process. Monoclonal antibodies are highly sensitive probes of protein conformation which can be used under these conditions. Here, we report the rescue of a diverse panel of 19 PrP-specific recombinant monoclonal antibodies from phage display libraries prepared from PrP deficient (Prnp0/0) mice immunized with infectious prions either in the form of rods or PrP 27-30 dispersed into liposomes. The antibodies recognize a number of distinct linear and discontinuous epitopes that are presented to a varying degree on different PrP preparations. The epitope reactivity of the recombinant PrP(90-231) molecule was almost indistinguishable from that of PrPC on the cell surface, validating the importance of detailed structural studies on the recombinant molecule. Only one epitope region at the C terminus of PrP was well presented on both PrPC and PrPSc, while epitopes associated with most of the antibodies in the panel were present on PrPCbut absent from PrPSc.

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Valdarnini, Niccolò, Bettina Holm, Paul Hansen, Paolo Rovero, Gunnar Houen, and Nicole Trier. "Fine Mapping of Glutamate Decarboxylase 65 Epitopes Reveals Dependency on Hydrophobic Amino Acids for Specific Interactions." International Journal of Molecular Sciences 20, no. 12 (June 14, 2019): 2909. http://dx.doi.org/10.3390/ijms20122909.

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Characterization of multiple antibody epitopes has revealed the necessity of specific groups of amino acid residues for reactivity. This applies to the majority of antibody–antigen interactions, where especially charged and hydrophilic amino acids have been reported to be essential for antibody reactivity. This study describes thorough characterization of glutamic acid decarboxylase (GAD) 65 antigenic epitopes, an immunodominant autoantigen in type 1 diabetes (T1D). As linear epitopes are sparsely described for GAD65 in T1D, we aimed to identify and thoroughly characterize two GAD65 antibodies using immunoassays. A monoclonal antibody recognized an epitope in the N-terminal domain of GAD65, 8FWSFGSE14, whereas a polyclonal antibody recognized two continuous epitopes in the C-terminal domain, corresponding to amino acids 514RTLED518 and 549PLGDKVNF556. Hydrophobic amino acids were essential for antibody reactivity, which was verified by competitive inhibition assays. Moreover, the epitopes were located in flexible linker regions and turn structures. These findings confirm the versatile nature of antibody–antigen interactions and describe potential continuous epitopes related to T1D, which predominantly have been proposed to be of discontinuous nature.

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Lisova, Olesia, Florence Hardy, Vincent Petit, and Hugues Bedouelle. "Mapping to completeness and transplantation of a group-specific, discontinuous, neutralizing epitope in the envelope protein of dengue virus." Journal of General Virology 88, no. 9 (September 1, 2007): 2387–97. http://dx.doi.org/10.1099/vir.0.83028-0.

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Dengue is caused by a taxonomic group of four viruses, dengue virus types 1–4 (DENV1–DENV4). A molecular understanding of the antibody-mediated protection against this disease is critical to design safe vaccines and therapeutics. Here, the energetic epitope of antibody mAb4E11, which neutralizes the four serotypes of DENV but no other flavivirus, and binds domain 3 (ED3) of their envelope glycoprotein, was characterized. Alanine-scanning mutagenesis of the ED3 domain from serotype DENV1 was performed and the affinities between the mutant domains and the Fab fragment of mAb4E11 were measured. The epitope residues (307–312, 387, 389 and 391) were at the edges of two distinct β-sheets. Four residues constituted hot spots of binding energy. They were aliphatic and contributed to form a hydrophobic pocket (Leu308, Leu389), or were positively charged (Lys307, Lys310). They may bind the diversity residues of mAb4E11, H-Trp96-Glu97. Remarkably, cyclic residues occupy and block the hydrophobic pocket in all unrelated flaviviruses. Transplanting the epitope from the ED3 domain of DENV into those of other flaviviruses restored affinity. The epitope straddles residues of ED3 that are involved in virulence, e.g. Asn/Asp390. These results define the epitope of mAb4E11 as an antigenic signature of the DENV group and suggest mechanisms for its neutralization potency.

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Smith, Michele, Jonathon Hoffman, Hakimuddin Sojar, Ravikumar Aalinkeel, Chiu-Bin Hsiao, and Mark Daniel Hicar. "Assessment of Antibody Interference of Enfuvirtide (T20) Function Shows Assay Dependent Variability." Current HIV Research 16, no. 6 (March 26, 2019): 404–15. http://dx.doi.org/10.2174/1570162x17666190228154850.

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Background:During HIV infection, fusion of the viral and cellular membranes is dependent on folding of the gp41 trimer into a six-helix bundle. Fusion inhibitors, such as the antiretroviral Enfuvirtide (T20), interfere with the formation of the gp41 six-helix bundle. Recent in vitro studies reveal that the gp41 immunodominant region one targeting antibody 3D6 can block T20 interference, but the clinical and pathophysiologic significance of this finding is unclear.Objective/Method:We have previously characterized a number of antibodies that target conformational epitopes on gp41and herein characterized their ability to interfere with T20 in multiple assays and assess their prevalence in HIV infected subjects.Results:The T20 interference by antibody 3D6 was confirmed in a CHO-HXB2 envelope/ HeLaT4+ cell culture assay. Antibodies that target an immunodominant region one epitope, as well as a gp41 discontinuous epitope, also interfered in this assay, however, not all antibodies that targeted these epitopes showed T20 interference. This response was not due to the direct binding of T20 by the antibodies and could not be replicated utilizing TZM-bl and HL2/3 cells. Notably, serum competition studies on a panel of HIV subjects demonstrate that these conformational targeting antibodies are common in the HIV population.Conclusion:The relatively common nature of antibodies targeting these epitopes, the disparate in vitro results, and lack of reported clinical failures ascribed to such antibodies leads us to conclude that antibody interference of T20 is likely not clinically relevant. However, this warrants continued consideration with the advancement of other fusion inhibitors.

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Meuleman, Theodorus J., Vanessa M. Cowton, Arvind H. Patel, and Rob M. J. Liskamp. "Design and Synthesis of HCV-E2 Glycoprotein Epitope Mimics in Molecular Construction of Potential Synthetic Vaccines." Viruses 13, no. 2 (February 20, 2021): 326. http://dx.doi.org/10.3390/v13020326.

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Hepatitis C virus remains a global threat, despite the availability of highly effective direct-acting antiviral (DAA) drugs. With thousands of new infections annually, the need for a prophylactic vaccine is evident. However, traditional vaccine design has been unable to provide effective vaccines so far. Therefore, alternative strategies need to be investigated. In this work, a chemistry-based approach is explored towards fully synthetic peptide-based vaccines using epitope mimicry, by focusing on highly effective and conserved amino acid sequences in HCV, which, upon antibody binding, inhibit its bio-activity. Continuous and discontinuous epitope mimics were both chemically synthesized based on the HCV-E2 glycoprotein while using designed fully synthetic cyclic peptides. These cyclic epitope mimics were assembled on an orthogonally protected scaffold. The scaffolded epitope mimics have been assessed in immunization experiments to investigate the elicitation of anti-HCV-E2 glycoprotein antibodies. The neutralizing potential of the elicited antibodies was investigated, representing a first step in employing chemically synthesized epitope mimics as a novel strategy towards vaccine design.

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B., Jesvin Bency, and Mary Helen P. A. "Novel epitope based peptides for vaccine against SARS-CoV-2 virus: immunoinformatics with docking approach." International Journal of Research in Medical Sciences 8, no. 7 (June 26, 2020): 2385. http://dx.doi.org/10.18203/2320-6012.ijrms20202875.

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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative viral strain for the contagious pandemic respiratory illness in humans which is a public health emergency of international concern. There is a desperate need for vaccines and antiviral strategies to combat the rapid spread of SARS-CoV-2 infection.Methods: The present study based on computational methods has identified novel conserved cytotoxic T-lymphocyte epitopes as well as linear and discontinuous B-cell epitopes on the SARS-CoV-2 spike (S) protein. The predicted MHC class I and class II binding peptides were further checked for their antigenic scores, allergenicity, toxicity, digesting enzymes and mutation.Results: A total of fourteen linear B-cell epitopes where GQSKRVDFC displayed the highest antigenicity-score and sixteen highly antigenic 100% conserved T-cell epitopes including the most potential vaccine candidates MHC class-I peptide KIADYNYKL and MHC class-II peptide VVFLHVTYV were identified. Furthermore, the potential peptide QGFSALEPL with high antigenicity score attached to larger number of human leukocyte antigen alleles. Docking analyses of the allele HLA-B*5201 predicted to be immunogenic to several of the selected epitopes revealed that the peptides engaged in strong binding with the HLA-B*5201 allele.Conclusions: Collectively, this research provides novel candidates for epitope-based peptide vaccine design against SARS-CoV-2 infection.

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Schramm, G., A. Bufe, A. Petersen, H. Haas, R. Merget, M. Schlaak, and W. M. Becker. "Discontinuous IgE-binding epitopes contain multiple continuous epitope regions: results of an epitope mapping on recombinant Hol l 5, a major allergen from velvet grass pollen." Clinical & Experimental Allergy 31, no. 2 (February 2001): 331–41. http://dx.doi.org/10.1046/j.1365-2222.2001.01049.x.

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Spindler, N., P. Rucker, S. Potzsch, U. Diestel, H. Sticht, L. Martin-Parras, T. H. Winkler, and M. Mach. "Characterization of a Discontinuous Neutralizing Epitope on Glycoprotein B of Human Cytomegalovirus." Journal of Virology 87, no. 16 (June 5, 2013): 8927–39. http://dx.doi.org/10.1128/jvi.00434-13.

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Thiel, Carsten, Klaus Weber, and Volker Gerke. "Characterization of a discontinuous epitope on annexin II by site-directed mutagenesis." FEBS Letters 285, no. 1 (July 8, 1991): 59–62. http://dx.doi.org/10.1016/0014-5793(91)80724-h.

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Crill, Wayne D., and Gwong-Jen J. Chang. "Localization and Characterization of Flavivirus Envelope Glycoprotein Cross-Reactive Epitopes." Journal of Virology 78, no. 24 (December 15, 2004): 13975–86. http://dx.doi.org/10.1128/jvi.78.24.13975-13986.2004.

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ABSTRACT The flavivirus E glycoprotein, the primary antigen that induces protective immunity, is essential for membrane fusion and mediates binding to cellular receptors. Human flavivirus infections stimulate virus species-specific as well as flavivirus cross-reactive immune responses. Flavivirus cross-reactive antibodies in human sera create a serious problem for serodiagnosis, especially for secondary flavivirus infections, due to the difficulty of differentiating primary from secondary cross-reactive serum antibodies. The presence of subneutralizing levels of flavivirus cross-reactive serum antibodies may result in a dramatic increase in the severity of secondary flavivirus infections via antibody-dependent enhancement. An understanding of flavivirus E-glycoprotein cross-reactive epitopes is therefore critical for improving public health responses to these serious diseases. We identified six E-glycoprotein residues that are incorporated into three distinct flavivirus cross-reactive epitopes. Two of these epitopes which are recognized by distinct monoclonal antibodies contain overlapping continuous residues located within the highly conserved fusion peptide. The third epitope consists of discontinuous residues that are structurally related to the strictly conserved tryptophan at dengue virus serotype 2 E-glycoprotein position 231.

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Chukwudozie, Onyeka S., Clive M. Gray, Tawakalt A. Fagbayi, Rebecca C. Chukwuanukwu, Victor O. Oyebanji, Taiwo T. Bankole, Richard A. Adewole, and Eze M. Daniel. "Immuno-informatics design of a multimeric epitope peptide based vaccine targeting SARS-CoV-2 spike glycoprotein." PLOS ONE 16, no. 3 (March 17, 2021): e0248061. http://dx.doi.org/10.1371/journal.pone.0248061.

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Developing an efficacious vaccine for SARS-CoV-2 infection is critical to stemming COVID-19 fatalities and providing the global community with immune protection. We have used a bioinformatic approach to aid in designing an epitope peptide-based vaccine against the spike protein of the virus. Five antigenic B cell epitopes with viable antigenicity and a total of 27 discontinuous B cell epitopes were mapped out structurally in the spike protein for antibody recognition. We identified eight CD8+ T cell 9-mers and 12 CD4+ T cell 14-15-mer as promising candidate epitopes putatively restricted by a large number of MHC I and II alleles, respectively. We used this information to construct an in silico chimeric peptide vaccine whose translational rate was highly expressed when cloned in pET28a (+) vector. With our In silico test, the vaccine construct was predicted to elicit high antigenicity and cell-mediated immunity when given as a homologous prime-boost, triggering of toll-like receptor 5 by the adjuvant linker. The vaccine was also characterized by an increase in IgM and IgG and an array of Th1 and Th2 cytokines. Upon in silico challenge with SARS-CoV-2, there was a decrease in antigen levels using our immune simulations. We, therefore, propose that potential vaccine designs consider this approach.

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Dall’Antonia, Fabio, and Walter Keller. "SPADE web service for prediction of allergen IgE epitopes." Nucleic Acids Research 47, W1 (May 8, 2019): W496—W501. http://dx.doi.org/10.1093/nar/gkz331.

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Abstract The specific interaction of allergens with IgE antibodies and the allergen mediated cross-linking of receptor-bound IgE are key events of allergic diseases. The elucidation of the IgE binding sites (the epitopes) on the allergen surface is an important goal of allergy research. Only few allergen-specific IgE epitopes have been determined experimentally to date. Epitope prediction methods represent a viable alternative to experimental methods and have worked well with linear epitopes. However, as most IgE epitopes are of conformational and/or discontinuous nature sequence based prediction methods have had limited success in these cases. Here, we present the web server of the program SPADE (https://spade.uni-graz.at), which is the server implementation of a previously published program (1). In this approach we utilize the structural homology of cross-reactive allergens combined with the immunological cross-reactivity data for the discrimination of putative IgE-binding sites from non-cross-reactive surface patches. The method, although predictive, does not rely on machine-learning algorithms and does not require training data. The SPADE server features an easy-to-use interface, an automated pipeline consisting of third-party, as well as own, newly developed routines and a comprehensive output page.

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Skraban, Robert, Sigrídur Matthíasdóttir, Sigurbjörg Torsteinsdóttir, Gudrún Agnarsdóttir, Bjarki Gudmundsson, Gudmundur Georgsson, Rob H. Meloen, et al. "Naturally Occurring Mutations within 39 Amino Acids in the Envelope Glycoprotein of Maedi-Visna Virus Alter the Neutralization Phenotype." Journal of Virology 73, no. 10 (October 1, 1999): 8064–72. http://dx.doi.org/10.1128/jvi.73.10.8064-8072.1999.

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ABSTRACT Infectious molecular clones have been isolated from two maedi-visna virus (MVV) strains, one of which (KV1772kv72/67) is an antigenic escape mutant of the other (LV1-1KS1). To map the type-specific neutralization epitope, we constructed viruses containing chimeric envelope genes by using KV1772kv72/67 as a backbone and replacing various parts of the envelope gene with equivalent sequences from LV1-1KS1. The neutralization phenotype was found to map to a region in the envelope gene containing two deletions and four amino acid changes within 39 amino acids (positions 559 to 597 of Env). Serum obtained from a lamb infected with a chimeric virus, VR1, containing only the 39 amino acids from LV1-1KS1 in the KV1772kv72/67 backbone neutralized LV1-1KS1 but not KV1772kv72/67. The region in the envelope gene that we had thus shown to be involved in escape from neutralization was cloned into pGEX-3X expression vectors, and the resulting fusion peptides from both molecular clones were tested in immunoblots for reactivity with the KV1772kv72/67 and VR1 type-specific antisera. The type-specific KV1772kv72/67 antiserum reacted only with the fusion peptide from KV1772kv72/67 and not with that from LV1-1KS1, and the type-specific VR1 antiserum reacted only with the fusion peptide from LV1-1KS1 and not with that from KV1772kv72/67. Pepscan analysis showed that the region contained two linear epitopes, one of which was specific to each of the molecularly cloned viruses. This linear epitope was not bound by all type-specific neutralizing antisera, however, which indicates that it is not by itself the neutralization epitope but may be a part of it. These findings show that mutations within amino acids 559 to 597 in the envelope gene of MVV virus result in escape from neutralization. Furthermore, the region contains one or more parts of a discontinuous neutralization epitope.

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He, R., DM Reid, CE Jones, and NR Shulman. "Extracellular epitopes of platelet glycoprotein Ib alpha reactive with serum antibodies from patients with chronic idiopathic thrombocytopenic purpura." Blood 86, no. 10 (November 15, 1995): 3789–96. http://dx.doi.org/10.1182/blood.v86.10.3789.bloodjournal86103789.

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Glycoproteins (GPs) IIb/IIIa and Ib/IX are principal targets of autoantibodies (autoAbs) in idiopathic thrombocytopenic purpura (ITP). Platelet-associated Abs against GPIIb/IIIa primarily recognize discontinuous or nonlinear epitopes (Fujisawa et al, Blood 81:1284, 1993). This study focused on whether Abs against the extracellular domain of GPIb/IX might react with short linear amino acid (aa) sequences of GPIb alpha. Complementary DNAs (cDNAs) coding for two overlapping fragments of GPIb alpha were amplified, cloned into pFLAG.2 plasmids, and expressed in Escherichia coli DH5 alpha competent cells as FLAG fusion proteins, which were purified by anti-FLAG immunoaffinity chromatography. Of 16 selected ITP sera containing anti- GPIb/IX, 6 reacted in microtiter radioimmunoassays (RIAs) with recombinant protein fragment 2 (aas 240 to 485); 1 also with fragment 1 (aas 1 to 247). When synthetic peptides corresponding to 4 segments of fragment 2 with high antigenic indices (P1 to P4) were used as targets in RIAs, all 6 sera reacted with P2 (aas 326 to 346); 1 also reacted with P4 (aas 389 to 412). P2 was shown to be present on the surface of intact platelets by adsorption studies, and anti-P2 was detected in direct eluates of platelets from ITP patients. Glycocalicin in solution effectively competed with immobilized P2 for anti-P2; P2 in solution was a less effective competitor. Epitope scanning with a panel of synthetic 15-mer peptides localized the P2 epitope to the sequence, TKEQTTFPP. Epitope definition may offer insight into the pathophysiology of and more specific treatments for ITP.

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Mulder, Gwenn E., H. (Linda) C. Quarles van Ufford, Jeroen van Ameijde, Arwin J. Brouwer, John A. W. Kruijtzer, and Rob M. J. Liskamp. "Scaffold optimization in discontinuous epitope containing protein mimics of gp120 using smart libraries." Organic & Biomolecular Chemistry 11, no. 16 (2013): 2676. http://dx.doi.org/10.1039/c3ob27470e.

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Sasamori, Eriko, Sachiko Suzuki, Mieko Kato, Yuichi Tagawa, and Yoshiro Hanyu. "Characterization of discontinuous epitope of prion protein recognized by the monoclonal antibody T2." Archives of Biochemistry and Biophysics 501, no. 2 (September 2010): 232–38. http://dx.doi.org/10.1016/j.abb.2010.06.025.

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Santos, Gabriel Menezes Costa dos, Carlos Roberto Alves, Marcelo Alves Pinto, Luciane Almeida Amado Leon, and Franklin Souza-Silva. "Detection of Antibodies against Hepatitis A Virus (HAV) by a Surface Plasmon Resonance (SPR) Biosensor: A New Diagnosis Tool Based on the Major HAV Capsid Protein VP1 (SPR-HAVP1)." Sensors 21, no. 9 (May 3, 2021): 3167. http://dx.doi.org/10.3390/s21093167.

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Hepatitis A (HA) is an acute human infectious disease caused by a positive single-stranded RNA virus (HAV). It is mainly acquired through the fecal–oral route and is primarily spread by contact between people and exposure to contaminated water and food. Recently, large outbreaks of HA have been reported by low and moderate endemicity countries, emphasizing its importance in public health and the need for rapid and large-scale diagnostic tests to support public health decisions on HA. This work proposes a new tool for HAV diagnosis based on the association of surface plasmonic resonance with major capsid protein VP1 (SPR-HAVP1 assay), detecting IgM antibodies for HAV in human serum samples. Structural analyses of VP1 B-lymphocyte epitopes showed continuous and discontinuous epitopes. The discontinuous epitopes were identified in the N-terminal region of the VP1 protein. Both epitope types in the VP1 protein were shown by the reactivity of VP1 in native and denaturing conditions to IgM anti-HAV, which was favorable to tests of VP1 in the SPR assays. SPR-HAVP1 assays showed good performance in the detection of IgM polyclonal antibody anti-HAV. These assays were performed using a COOH5 sensor chip functionalized with VP1 protein. The sensorgram record showed a significant difference between positive and negative serum samples, which was confirmed by analysis of variation of initial and final dissociation values through time (ΔRUd/t). The data gathered here are unequivocal evidence that the SPR-HAVP1 strategy can be applied to detect IgM antibodies in human serum positive to the HAV. This is a new tool to be explored to diagnose human HAV infections.

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Rhodin, Nikki R., Jenny M. Cutalo, Kenneth B. Tomer, William P. McArthur, and L. Jeannine Brady. "Characterization of the Streptococcus mutans P1 Epitope Recognized by Immunomodulatory Monoclonal Antibody 6-11A." Infection and Immunity 72, no. 8 (August 2004): 4680–88. http://dx.doi.org/10.1128/iai.72.8.4680-4688.2004.

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ABSTRACT Monoclonal antibody (MAb) 6-11A directed against Streptococcus mutans surface adhesin P1 was shown previously to influence the mucosal immunogenicity of this organism in BALB/c mice. The specificity of anti-P1 serum immunoglobulin G (IgG) and secretory IgA antibodies and the subclass distribution of anti-P1 serum IgG antibodies were altered, and the ability of elicited serum antibodies to inhibit S. mutans adherence in vitro was in certain cases increased. MAb 6-11A is known to recognize an epitope dependent on the presence of the proline-rich region of the protein, although it does not bind directly to the isolated P-region domain. In this report, we show that MAb 6-11A recognizes a complex discontinuous epitope that requires the simultaneous presence of the alanine-rich repeat domain (A-region) and the P-region. Formation of the core epitope requires the interaction of these segments of P1. Residues amino terminal to the A-region also contributed to recognition by MAb 6-11A but were not essential for binding. Characterization of the MAb 6-11A epitope will enable insight into potential mechanisms of immunomodulation and broaden our understanding of the tertiary structure of P1.

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Poignard, P., T. Fouts, D. Naniche, J. P. Moore, and Q. J. Sattentau. "Neutralizing antibodies to human immunodeficiency virus type-1 gp120 induce envelope glycoprotein subunit dissociation." Journal of Experimental Medicine 183, no. 2 (February 1, 1996): 473–84. http://dx.doi.org/10.1084/jem.183.2.473.

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The spectrum of the anti-human immunodeficiency virus (HIV) neutralizing immune response has been analyzed by the production and characterization of monoclonal antibodies (mAbs) to the viral envelope glycoproteins, gp41 and gp120. Little is known, however, about the neutralization mechanism of these antibodies. Here we show that the binding of a group of neutralizing mAbs that react with regions of the gp120 molecule associated with and including the V2 and V3 loops, the C4 domain and supporting structures, induce the dissociation of gp120 from gp41 on cells infected with the T cell line-adapted HIV-1 molecular clone Hx10. Similar to soluble receptor-induced dissociation of gp120 from gp41, the antibody-induced dissociation is dose- and time-dependent. By contrast, mAbs binding to discontinuous epitopes overlapping the CD4 binding site do not induce gp120 dissociation, implying that mAb induced conformational changes in gp120 are epitope specific, and that HIV neutralization probably involves several mechanisms.

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Rafalik, M., M. Spodzieja, A. S. Kołodziejczyk, S. Rodziewicz-Motowidło, A. Szymańska, A. Grubb, and P. Czaplewska. "The identification of discontinuous epitope in the human cystatin C – Monoclonal antibody HCC3 complex." Journal of Proteomics 191 (January 2019): 58–67. http://dx.doi.org/10.1016/j.jprot.2018.04.020.

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Manijeh, Mahdavi, Moreau Violaine, Jafarian Dehkordi Abbas, Keyhanfar Mehrnaz, Mohabbatkar Hassan, and Rabbani Mohammad. "Identification of discontinuous B cell epitope peptide vaccines from HER2 ECD by bioinformatics methods." New Biotechnology 29 (September 2012): S29. http://dx.doi.org/10.1016/j.nbt.2012.08.073.

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Manije, Mahdavi, Moreau Violaine, Jafarian Dehkordi, Abbas Keyhanfar Mehrnaz, Mohabbatkar Hassan, and Rabbani Mohammad. "Identification of discontinuous B cell epitope peptide vaccines from HER2 ECD by bioinformatics methods." New Biotechnology 29 (September 2012): S143. http://dx.doi.org/10.1016/j.nbt.2012.08.397.

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van Dolleweerd, Craig J., Charles G. Kelly, Daniel Chargelegue, and Julian K.-C. Ma. "Peptide Mapping of a Novel Discontinuous Epitope of the Major Surface Adhesin fromStreptococcus mutans." Journal of Biological Chemistry 279, no. 21 (April 1, 2004): 22198–203. http://dx.doi.org/10.1074/jbc.m400820200.

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Enshell-Seijffers, David, Dmitri Denisov, Bella Groisman, Larisa Smelyanski, Ronit Meyuhas, Gideon Gross, Galina Denisova, and Jonathan M. Gershoni. "The Mapping and Reconstitution of a Conformational Discontinuous B-cell Epitope of HIV-1." Journal of Molecular Biology 334, no. 1 (November 2003): 87–101. http://dx.doi.org/10.1016/j.jmb.2003.09.002.

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Messer, William B., Boyd L. Yount, Scott R. Royal, Ruklanthi de Alwis, Douglas G. Widman, Scott A. Smith, James E. Crowe, et al. "Functional Transplant of a Dengue Virus Serotype 3 (DENV3)-Specific Human Monoclonal Antibody Epitope into DENV1." Journal of Virology 90, no. 10 (March 9, 2016): 5090–97. http://dx.doi.org/10.1128/jvi.00155-16.

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ABSTRACTThe four dengue virus (DENV) serotypes, DENV1 through 4, are endemic throughout tropical and subtropical regions of the world. While first infection confers long-term protective immunity against viruses of the infecting serotype, a second infection with virus of a different serotype carries a greater risk of severe dengue disease, including dengue hemorrhagic fever and dengue shock syndrome. Recent studies demonstrate that humans exposed to DENV infections develop neutralizing antibodies that bind to quaternary epitopes formed by the viral envelope (E) protein dimers or higher-order assemblies required for the formation of the icosahedral viral envelope. Here we show that the quaternary epitope target of the human DENV3-specific neutralizing monoclonal antibody (MAb) 5J7 can be partially transplanted into a DENV1 strain by changing the core residues of the epitope contained within a single monomeric E molecule. MAb 5J7 neutralized the recombinant DENV1/3 strain in cell culture and was protective in a mouse model of infection with the DENV1/3 strain. However, the 5J7 epitope was only partially recreated by transplantation of the core residues because MAb 5J7 bound and neutralized wild-type (WT) DENV3 better than the DENV1/3 recombinant. Our studies demonstrate that it is possible to transplant a large number of discontinuous residues between DENV serotypes and partially recreate a complex antibody epitope, while retaining virus viability. Further refinement of this approach may lead to new tools for measuring epitope-specific antibody responses and new vaccine platforms.IMPORTANCEDengue virus is the most important mosquito-borne pathogen of humans worldwide, with approximately one-half the world's population living in regions where dengue is endemic. Dengue immunity following infection is robust and thought to be conferred by antibodies raised against the infecting virus. However, the specific viral components that these antibodies recognize and how they neutralize the virus have been incompletely described. Here we map a region on dengue virus serotype 3 recognized by the human neutralizing antibody 5J7 and then test the functional significance of this region by transplanting it into a serotype 1 virus. Our studies demonstrate a region on dengue virus necessary for 5J7 binding and neutralization. Our work also demonstrates the technical feasibility of engineering dengue viruses to display targets of protective antibodies. This technology can be used to develop new dengue vaccines and diagnostic assays.

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Sweredoski, Michael J., and Pierre Baldi. "PEPITO: improved discontinuous B-cell epitope prediction using multiple distance thresholds and half sphere exposure." Bioinformatics 24, no. 12 (April 28, 2008): 1459–60. http://dx.doi.org/10.1093/bioinformatics/btn199.

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Costagliola, Sabine, Marco Bonomi, Nils G. Morgenthaler, Joost Van Durme, Valérie Panneels, Samuel Refetoff, and Gilbert Vassart. "Delineation of the Discontinuous-Conformational Epitope of a Monoclonal Antibody Displaying Fullin Vitroandin VivoThyrotropin Activity." Molecular Endocrinology 18, no. 12 (December 2004): 3020–34. http://dx.doi.org/10.1210/me.2004-0231.

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Szewczuk, Z., A. Wilczyński, I. Petry, I. Z. Siemion, and Z. Wieczorek. "Design, synthesis and biological evaluation of a new bridged immunosuppressor." Acta Biochimica Polonica 48, no. 4 (December 31, 2001): 1147–50. http://dx.doi.org/10.18388/abp.2001_3881.

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A bridged peptide with the sequence: H-Thr-Pro-Gln-Arg-Gly-Asp-Val-gamma-Abu-Asn-Asp-Gln-Glu-Glu-Thr-Thr-Gly-Val-Val-Ser-Thr-Pro-Leu-Ile-Arg-Asn-Gly-OH was designed to mimic the discontinuous epitope of the HLA-DQ molecule that might interact with CD4. The bridged peptide revealed distinct suppressory effect in the humoral immune response. This result supports our suggestion that the 164-172 region of the HLA-DQ molecule may enhance its interactions with coreceptors, possibly with CD4.

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Rouka, Erasmia, Konstantinos I. Gourgoulianis, and Sotirios G. Zarogiannis. "In silico investigation of the viroporin E as a vaccine target against SARS-CoV-2." American Journal of Physiology-Lung Cellular and Molecular Physiology 320, no. 6 (June 1, 2021): L1057—L1063. http://dx.doi.org/10.1152/ajplung.00443.2020.

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Viroporins, integral viral membrane ion channel proteins, interact with host-cell proteins deregulating physiological processes and activating inflammasomes. Severity of COVID-19 might be associated with hyperinflammation, thus we aimed at the complete immunoinformatic analysis of the SARS-CoV-2 viroporin E, P0DTC4. We also identified the human proteins interacting with P0DTC4 and the enriched molecular functions of the corresponding genes. The complete sequence of P0DTC4 in FASTA format was processed in 10 databases relative to secondary and tertiary protein structure analyses and prediction of optimal vaccine epitopes. Three more databases were accessed for the retrieval and the molecular functional characterization of the P0DTC4 human interactors. The immunoinformatics analysis resulted in the identification of 4 discontinuous B-cell epitopes along with 1 linear B-cell epitope and 11 T-cell epitopes which were found to be antigenic, immunogenic, nonallergen, nontoxin, and unable to induce autoimmunity thus fulfilling prerequisites for vaccine design. The functional enrichment analysis showed that the predicted host interactors of P0DTC4 target the cellular acetylation network. Two of the identified host-cell proteins – BRD2 and BRD4 – have been shown to be promising targets for antiviral therapy. Thus, our findings have implications for COVID-19 therapy and indicate that viroporin E could serve as a promising vaccine target against SARS-CoV-2. Validation experiments are required to complement these in silico results.

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Journal articles on the topic 'Discontinuous epitope'

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