{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T10:05:03Z","timestamp":1769767503506,"version":"3.49.0"},"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondo de Cooperaci\u00c3\u00b3n Internacional en Ciencia y Tecnolog\u00c3a\u201d CONACYT-BMBF 2016","award":["FONCICYT-291205"],"award-info":[{"award-number":["FONCICYT-291205"]}]},{"name":"Laboratorio Nacional de C\u00c3\u00b3mputo de Alto Desempe\u00c3\u00b1o","award":["LANCAD-UNAM-DGTIC-286"],"award-info":[{"award-number":["LANCAD-UNAM-DGTIC-286"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>The Zika virus (ZIKV) poses a significant public health threat, and developing highly specific diagnostic and therapeutic agents that can distinguish it from other flaviviruses remains a critical challenge. To address this, we utilized a phage display library with a strategic subtractive panning approach against the ZIKV envelope protein (ZIKV-pE). This method identified eight linear peptides with high binding ability for ZIKV-pE. Enzyme-linked immunosorbent assay (ELISA) confirmed that these peptides recognized ZIKV-pE with statistical significance compared to a bovine serum albumin (BSA) control. To elucidate the binding mechanisms, we performed molecular docking and molecular dynamics (MD) simulations. Computational analysis identified peptides R3Z15, R3Z09, R2Z05, and R3Z02 as the top candidates based on binding free energy calculations. The simulations revealed that these peptides bind specifically to the DIII domain of ZIKV-pE primarily via electrostatic interactions and form stable complexes over 300 ns of MD simulation. Our work identifies specific, high-affinity peptide binders to ZIKV-pE. It provides a structural basis for their selectivity, positioning them as promising candidates for the development of precise ZIKV diagnostics and targeted therapeutics.<\/jats:p>","DOI":"10.1371\/journal.pone.0341602","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T18:26:56Z","timestamp":1769711216000},"page":"e0341602","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery and computational characterization of ZIKV envelope-targeted peptides from a subtractive phage display library"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9095-3563","authenticated-orcid":true,"given":"Mirna","family":"Burciaga-Flores","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Wong-Romero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darwin","family":"Elizondo-Quiroga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Er\u00e9ndira","family":"Villalobos-S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abel","family":"Guti\u00e9rrez-Ortega","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanya A.","family":"Camacho-Villegas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8497-2821","authenticated-orcid":true,"given":"Sergio A.","family":"\u00c1guila","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"issue":"1","key":"pone.0341602.ref001","doi-asserted-by":"crossref","first-page":"47","DOI":"10.3390\/ijms26010047","article-title":"An overview of zika virus and zika virus induced neuropathies","volume":"26","author":"A Wahaab","year":"2024","journal-title":"Int J Mol Sci"},{"issue":"1","key":"pone.0341602.ref002","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1186\/s12985-024-02547-z","article-title":"Zika virus tropism and pathogenesis: understanding clinical impacts and transmission dynamics","volume":"21","author":"S Tajik","year":"2024","journal-title":"Virol J"},{"issue":"17","key":"pone.0341602.ref003","doi-asserted-by":"crossref","first-page":"9424","DOI":"10.3390\/ijms25179424","article-title":"Envelope protein-targeting zika virus entry inhibitors","volume":"25","author":"A Roy","year":"2024","journal-title":"Int J Mol Sci"},{"key":"pone.0341602.ref004","doi-asserted-by":"crossref","first-page":"2725","DOI":"10.3389\/fmicb.2019.02725","article-title":"Development of small-molecule inhibitors against zika virus infection","volume":"10","author":"L Wang","year":"2019","journal-title":"Front Microbiol"},{"key":"pone.0341602.ref005","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.3389\/fmicb.2017.02677","article-title":"Advances in diagnosis, surveillance, and monitoring of zika virus: an update","volume":"8","author":"RK Singh","year":"2018","journal-title":"Front Microbiol"},{"issue":"6","key":"pone.0341602.ref006","first-page":"344","article-title":"Updating Zika diagnostic methods: the point-of-care approach","volume":"72","author":"M Burciaga-Flores","year":"2020","journal-title":"Rev Invest Clin"},{"issue":"8","key":"pone.0341602.ref007","doi-asserted-by":"crossref","first-page":"865","DOI":"10.3390\/vaccines12080865","article-title":"The Flavivirus Non-Structural Protein 5 (NS5): structure, functions, and targeting for development of vaccines and therapeutics","volume":"12","author":"JZH Goh","year":"2024","journal-title":"Vaccines (Basel)"},{"issue":"9","key":"pone.0341602.ref008","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.02423-20","article-title":"A novel antigenic site spanning domains I and III of the zika virus envelope glycoprotein is the target of strongly neutralizing human monoclonal antibodies","volume":"95","author":"SD Graham","year":"2021","journal-title":"J Virol"},{"issue":"33","key":"pone.0341602.ref009","doi-asserted-by":"crossref","first-page":"4287","DOI":"10.1016\/j.vaccine.2017.04.052","article-title":"Immunization of Zika virus envelope protein domain III induces specific and neutralizing immune responses against Zika virus","volume":"35","author":"M Yang","year":"2017","journal-title":"Vaccine"},{"issue":"1","key":"pone.0341602.ref010","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s12985-020-01313-1","article-title":"Investigation of the immunogenicity of Zika glycan loop","volume":"17","author":"EA Henderson","year":"2020","journal-title":"Virol J"},{"issue":"6301","key":"pone.0341602.ref011","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1126\/science.aaf8505","article-title":"Specificity, cross-reactivity, and function of antibodies elicited by Zika virus infection","volume":"353","author":"K Stettler","year":"2016","journal-title":"Science"},{"key":"pone.0341602.ref012","doi-asserted-by":"crossref","first-page":"1071041","DOI":"10.3389\/fimmu.2023.1071041","article-title":"Diagnostic and vaccine potential of Zika virus envelope protein (E) derivates produced in bacterial and insect cells","volume":"14","author":"VAS Lunardelli","year":"2023","journal-title":"Front Immunol"},{"issue":"12","key":"pone.0341602.ref013","article-title":"Delineating antibody recognition against Zika virus during natural infection","volume":"2","author":"L Yu","year":"2017","journal-title":"JCI Insight"},{"issue":"10","key":"pone.0341602.ref014","article-title":"Neutralization of Zika virus by germline-like human monoclonal antibodies targeting cryptic epitopes on envelope domain III","volume":"6","author":"Y Wu","year":"2017","journal-title":"Emerg Microbes Infect"},{"issue":"2","key":"pone.0341602.ref015","doi-asserted-by":"crossref","first-page":"492","DOI":"10.3390\/ijms21020492","article-title":"Expression, Purification, and Characterization of Anti-Zika virus Envelope Protein: Polyclonal and Chicken-Derived Single Chain Variable Fragment Antibodies","volume":"21","author":"PF Mwale","year":"2020","journal-title":"Int J Mol Sci"},{"key":"pone.0341602.ref016","doi-asserted-by":"crossref","first-page":"975398","DOI":"10.3389\/fcimb.2022.975398","article-title":"Serological cross-reactivity among common flaviviruses","volume":"12","author":"KR Chan","year":"2022","journal-title":"Front Cell Infect Microbiol"},{"key":"pone.0341602.ref017","first-page":"1150","article-title":"Computational analysis of perturbations in the post-fusion Dengue virus envelope protein highlights known epitopes and conserved residues in the Zika virus","volume":"5","author":"S Chakraborty","year":"2016","journal-title":"F1000Res"},{"issue":"2","key":"pone.0341602.ref018","doi-asserted-by":"crossref","DOI":"10.1093\/femsre\/fuab052","article-title":"Phage display and other peptide display technologies","volume":"46","author":"W Jaroszewicz","year":"2022","journal-title":"FEMS Microbiol Rev"},{"issue":"9","key":"pone.0341602.ref019","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/s41573-022-00495-3","article-title":"Antibodies to combat viral infections: development strategies and progress","volume":"21","author":"G Pantaleo","year":"2022","journal-title":"Nat Rev Drug Discov"},{"issue":"1","key":"pone.0341602.ref020","doi-asserted-by":"crossref","DOI":"10.1093\/jambio\/lxac012","article-title":"The use of phage display systems to combat infectious diseases in poultry: diagnostic, vaccine, and therapeutic approaches","volume":"134","author":"\u0141 Grabowski","year":"2023","journal-title":"J Appl Microbiol"},{"issue":"6","key":"pone.0341602.ref021","doi-asserted-by":"crossref","first-page":"640","DOI":"10.3390\/bios13060640","article-title":"Antibody phage display technology for sensor-based virus detection: current status and future prospects","volume":"13","author":"OI Guliy","year":"2023","journal-title":"Biosensors (Basel)"},{"key":"pone.0341602.ref022","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.molimm.2018.11.016","article-title":"Selection and characterization of protective anti-chikungunya virus single domain antibodies","volume":"105","author":"JL Liu","year":"2019","journal-title":"Mol Immunol"},{"issue":"7","key":"pone.0341602.ref023","doi-asserted-by":"crossref","first-page":"3768","DOI":"10.1073\/pnas.1914985117","article-title":"Development of an antibody cocktail for treatment of Sudan virus infection","volume":"117","author":"AS Herbert","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"pone.0341602.ref024","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.3390\/v13061120","article-title":"Discovery of antivirals using phage display","volume":"13","author":"E Sokullu","year":"2021","journal-title":"Viruses"},{"issue":"7","key":"pone.0341602.ref025","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0180669","article-title":"Isolation of serotype-specific antibodies against dengue virus non-structural protein 1 using phage display and application in a multiplexed serotyping assay","volume":"12","author":"K Lebani","year":"2017","journal-title":"PLoS One"},{"issue":"8","key":"pone.0341602.ref026","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.1111\/febs.16419","article-title":"Impact of structural dynamics on biological functions of flaviviruses","volume":"290","author":"K Stiasny","year":"2023","journal-title":"FEBS J"},{"issue":"15","key":"pone.0341602.ref027","doi-asserted-by":"crossref","first-page":"12144","DOI":"10.3390\/ijms241512144","article-title":"Accelerating the screening of small peptide ligands by combining peptide-protein docking and machine learning","volume":"24","author":"J-R Codina","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"9","key":"pone.0341602.ref028","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.3390\/biom14091073","article-title":"Integrating computational design and experimental approaches for next-generation biologics","volume":"14","author":"A Son","year":"2024","journal-title":"Biomolecules"},{"issue":"2","key":"pone.0341602.ref029","doi-asserted-by":"crossref","first-page":"181","DOI":"10.2174\/138920308783955234","article-title":"Molecular dynamics simulations of proteins and peptides: from folding to drug design","volume":"9","author":"G Morra","year":"2008","journal-title":"Curr Protein Pept Sci"},{"key":"pone.0341602.ref030","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1385\/1-59259-890-0:571","article-title":"Protein identification and analysis tools on the ExPASy server","author":"E Gasteiger","year":"2005","journal-title":"The Proteomics Protocols Handbook. Humana Press"},{"issue":"1","key":"pone.0341602.ref031","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1038\/s41467-023-38039-x","article-title":"Engineering protein-based therapeutics through structural and chemical design","volume":"14","author":"SB Ebrahimi","year":"2023","journal-title":"Nat Commun"},{"issue":"6","key":"pone.0341602.ref032","doi-asserted-by":"crossref","first-page":"3036","DOI":"10.1021\/acs.jmedchem.8b01925","article-title":"Electrostatic complementarity as a fast and effective tool to optimize binding and selectivity of protein-ligand complexes","volume":"62","author":"MR Bauer","year":"2019","journal-title":"J Med Chem"},{"issue":"5","key":"pone.0341602.ref033","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA methods to estimate ligand-binding affinities","volume":"10","author":"S Genheden","year":"2015","journal-title":"Expert Opin Drug Discov"},{"key":"pone.0341602.ref034","doi-asserted-by":"crossref","first-page":"341300","DOI":"10.1016\/j.aca.2023.341300","article-title":"Biopanning of specific peptide for SARS-CoV-2 nucleocapsid protein and enzyme-linked immunosorbent assay-based antigen assay","volume":"1264","author":"P Ma","year":"2023","journal-title":"Anal Chim Acta"},{"issue":"1","key":"pone.0341602.ref035","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1080\/22221751.2022.2082888","article-title":"Identification and characterization of key residues in Zika virus envelope protein for virus assembly and entry","volume":"11","author":"X Ma","year":"2022","journal-title":"Emerg Microbes Infect"},{"issue":"27","key":"pone.0341602.ref036","doi-asserted-by":"crossref","first-page":"10638","DOI":"10.1074\/jbc.RA119.007443","article-title":"Characterization of two engineered dimeric Zika virus envelope proteins as immunogens for neutralizing antibody selection and vaccine design","volume":"294","author":"C Yang","year":"2019","journal-title":"J Biol Chem"},{"issue":"3","key":"pone.0341602.ref037","doi-asserted-by":"crossref","first-page":"72","DOI":"10.3390\/vaccines7030072","article-title":"Zika Virus-Derived E-DIII protein displayed on immunologically optimized VLPs induces neutralizing antibodies without causing enhancement of dengue virus infection","volume":"7","author":"G Cabral-Miranda","year":"2019","journal-title":"Vaccines (Basel)"},{"issue":"21","key":"pone.0341602.ref038","doi-asserted-by":"crossref","DOI":"10.1002\/cbic.202200351","article-title":"Initial recognition and attachment of the zika virus to host cells: a molecular dynamics and quantum interaction approach","volume":"23","author":"SA G\u00f3mez","year":"2022","journal-title":"Chembiochem"},{"issue":"11","key":"pone.0341602.ref039","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.3390\/cells8111444","article-title":"The Envelope Residues E152\/156\/158 of Zika Virus Influence the Early Stages of Virus Infection in Human Cells","volume":"8","author":"S Bos","year":"2019","journal-title":"Cells"},{"issue":"11","key":"pone.0341602.ref040","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.3390\/v12111258","article-title":"Immune reactivity of a 20-mer peptide representing the Zika E glycan loop involves the antigenic determinants E-152\/156\/158","volume":"12","author":"E Frumence","year":"2020","journal-title":"Viruses"},{"issue":"8","key":"pone.0341602.ref041","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1021\/acs.biochem.6b01056","article-title":"Interaction of zika virus envelope protein with glycosaminoglycans","volume":"56","author":"SY Kim","year":"2017","journal-title":"Biochemistry"},{"key":"pone.0341602.ref042","doi-asserted-by":"crossref","first-page":"104876","DOI":"10.1016\/j.antiviral.2020.104876","article-title":"Small molecule inhibitors possibly targeting the rearrangement of Zika virus envelope protein","volume":"182","author":"N Sharma","year":"2020","journal-title":"Antiviral Res"},{"key":"pone.0341602.ref043","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.coviro.2020.07.006","article-title":"Mapping the diverse structural landscape of the flavivirus antibody repertoire","volume":"45","author":"M Sevvana","year":"2020","journal-title":"Curr Opin Virol"},{"issue":"3","key":"pone.0341602.ref044","doi-asserted-by":"crossref","first-page":"935","DOI":"10.3390\/pharmaceutics15030935","article-title":"Designing formulation strategies for enhanced stability of therapeutic peptides in aqueous solutions: a review","volume":"15","author":"P Nugrahadi","year":"2023","journal-title":"Pharmaceutics"},{"key":"pone.0341602.ref045","article-title":"PEP-FOLD4: a pH-dependent force field for peptide structure prediction in aqueous solution","volume":"51","author":"J Rey","year":"2023","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"pone.0341602.ref046","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.chom.2016.04.013","article-title":"Structures of the zika virus envelope protein and its complex with a flavivirus broadly protective antibody","volume":"19","author":"L Dai","year":"2016","journal-title":"Cell Host Microbe"},{"key":"pone.0341602.ref047","volume-title":"Schr\u00f6dinger release 2024-3: Maestro","year":"2024"},{"key":"pone.0341602.ref048","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gky357","article-title":"HPEPDOCK: a web server for blind peptide-protein docking based on a hierarchical algorithm","volume":"46","author":"P Zhou","year":"2018","journal-title":"Nucleic Acids Res"},{"issue":"4","key":"pone.0341602.ref049","doi-asserted-by":"crossref","first-page":"044130","DOI":"10.1063\/5.0014475","article-title":"Scalable molecular dynamics on CPU and GPU architectures with NAMD","volume":"153","author":"JC Phillips","year":"2020","journal-title":"J Chem Phys"},{"issue":"11","key":"pone.0341602.ref050","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1021\/acs.jpcb.8b12419","article-title":"Dynamic docking of a medium-sized molecule to its receptor by multicanonical MD simulations","volume":"123","author":"G-J Bekker","year":"2019","journal-title":"J Phys Chem B"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0341602","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T18:27:08Z","timestamp":1769711228000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0341602"}},"subtitle":[],"editor":[{"given":"Pierre","family":"Roques","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,1,29]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1,29]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0341602","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,29]]}}}