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

• 成果类型: Article
• 署名作者: 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.
• 署名单位: Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Universidade Federal de Pernambuco; Fundacao Oswaldo Cruz; Texas A&M University System; Texas A&M University College Station; Universidade Federal da Bahia; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12357
• DOI: 10.1073/pnas.2312755121
• 发表日期: 2024-05-21
• 关键词: infection; antibodies; libraries

摘要

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.