{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:43:34Z","timestamp":1791333814100,"version":"4.3.1"},"posted":{"date-parts":[[2025,6,20]]},"group-title":"Microbiology","reference-count":38,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T00:00:00Z","timestamp":1750377600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"crossref","award":["U19AI171399"],"award-info":[{"award-number":["U19AI171399"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"name":"FWO Hercules Foundation","award":["ZW13-02"],"award-info":[{"award-number":["ZW13-02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,11]]},"abstract":"<jats:p>\n                  Flaviviruses are a class of pathogenic viruses with pandemic potential that are typically transmitted via infected arthropods. In addition, Zika virus is sexually transmissible and causes congenital malformations if infection occurs during pregnancy. Although over 1.5 million people were infected during the 2015-2016 Zika outbreak, to date, there are no clinical-stage vaccines or antivirals. Herein, we report the discovery of potent inhibitors of the Zika virus NS2B-NS3 protease that also show activity against the West Nile virus NS2B-NS3 protease. Starting from a crystallographic fragment screen, we employed a pharmacophore approach coupled with high-throughput library chemistry to elaborate fragments in the active site. Potent, metabolically stable, non-covalent, non-peptidomimetic inhibitors were identified with antiviral activity\n                  <jats:italic>in vitro<\/jats:italic>\n                  . The lead compound was progressed to a three-day Zika virus challenge study in AG129 mice, where it displayed significant viral RNA load reduction in both mouse plasma and spleen.\n                <\/jats:p>","DOI":"10.1101\/2025.06.19.660642","type":"posted-content","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T23:56:11Z","timestamp":1750463771000},"source":"Crossref","is-referenced-by-count":3,"title":["Discovery of orally bioavailable Zika virus NS2B-NS3 protease inhibitors with efficacy in a murine infection model"],"prefix":"10.64898","author":[{"given":"Nathaniel T.","family":"Kenton","sequence":"first","affiliation":[{"name":"PostEra Inc, 1 Broadway, Cambridge MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haim","family":"Barr","sequence":"additional","affiliation":[{"name":"The Wohl Drug Discovery Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 7610001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artem","family":"Cherepakha","sequence":"additional","affiliation":[{"name":"Enamine Ltd., 78 Winston Churchill Street, 02094 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lotte","family":"Coelmont","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Virology, Antiviral Drug & Vaccine Research Group, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Collard","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Virology, Antiviral Drug & Vaccine Research Group, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Cousins","sequence":"additional","affiliation":[{"name":"MedChemica Consultancy Ltd, Macclesfield, Cheshire, SK11 6DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraint H. 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