Identification and characterization of a nonbiological small-molecular mimic of a Zika virus conformational neutralizing epitope

• Published in: Proceedings of the National Academy of Sciences - PNAS 2024-05, Vol.121 (21), p.e2312755121-e2312755121
• Main Authors: Castanha, Priscila M S, McEnaney, Patrick J, Park, Yongseok, Bouwer, Anthea, Chaves, Elton J F, Lins, Roberto D, Paciaroni, Nicholas G, Dickson, Paige, Carlson, Graham, Cordeiro, Marli T, Magalhaes, Tereza, Craigo, Jodi, Marques, Ernesto T A, Kodadek, Thomas, Burke, Donald S
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - immunology; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Antisera; Biological Sciences; Combinatorial analysis; Deoxyribonucleic acid; DNA; DNA sequencing; DNA vaccines; Epitopes; Epitopes - immunology; Gene sequencing; Humans; Immunoglobulin G; Immunoglobulin G - immunology; Molecular Mimicry - immunology; Molecular structure; Monoclonal antibodies; Neutralizing; Vector-borne diseases; Viruses; Zika virus; Zika Virus - immunology; Zika Virus Infection - immunology; Zika Virus Infection - virology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2312755121

Antigenic similarities between Zika virus (ZIKV) and other flaviviruses pose challenges to the development of virus-specific diagnostic tools and effective vaccines. Starting with a DNA-encoded one-bead-one-compound combinatorial library of 508,032 synthetic, non-natural oligomers, we selected and characterized small molecules that mimic ZIKV epitopes. High-throughput fluorescence-activated cell sorter-based bead screening was used to select molecules that bound IgG from ZIKV-immune but not from dengue-immune sera. Deep sequencing of the DNA from the "Zika-only" beads identified 40 candidate molecular structures. A lead candidate small molecule "CZV1-1" was selected that correctly identifies serum specimens from Zika-experienced patients with good sensitivity and specificity (85.3% and 98.4%, respectively). Binding competition studies of purified anti-CZV1-1 IgG against known ZIKV-specific monoclonal antibodies (mAbs) showed that CZV1-1 mimics a nonlinear, neutralizing conformational epitope in the domain III of the ZIKV envelope. Purified anti-CZV1-1 IgG neutralized infection of ZIKV in cell cultures with potencies comparable to highly specific ZIKV-neutralizing mAbs. This study demonstrates an innovative approach for identification of synthetic non-natural molecular mimics of conformational virus epitopes. Such molecular mimics may have value in the development of accurate diagnostic assays for Zika, as well as for other viruses.