2. Academic Validation
  3. Discovery of orally bioavailable Zika and West Nile Virus antiviral compounds targeting the NS2B-NS3 protease

Discovery of orally bioavailable Zika and West Nile Virus antiviral compounds targeting the NS2B-NS3 protease

  • bioRxiv. 2025 Jun 20:2025.06.19.660642. doi: 10.1101/2025.06.19.660642.
Nathaniel T Kenton 1,  Haim Barr 2,  Artem Cherepakha 3,  Lotte Coelmont 4,  Caroline Collard 4,  David Cousins 5,  Geraint H M Davies 1,  Oleksii Degtyarenko 3,  Andrew Dirksen 1,  Daniel Elbrecht 1,  Daren Fearon 6,  James Gayvert 1,  Edward Griffen 5,  Dirk Jochmans 4,  Suzanne Kaptein 4,  Pavlo Kliatskiy 3,  Artem Kochetkov 3,  Mykyta Kordubailo 3,  Noa Lahav 2,  Nir London 2,  Elke Maas 4,  Peter Marples 6,  Nataliya Nady 1,  Johan Neyts 4,  Luong Nguyen 1,  Xiaomin Ni 7,  Yuliia Ogorodnik 3,  Matthew C Robinson 1,  Carolina Turk Simpson 1,  Ihor Tarabara 3,  Anton Tkachenko 3,  Annette von Delft 7,  Frank von Delft 6 7 8 9,  Oleksandr Yakymenko 3,  Alpha A Lee 1
Affiliations

Affiliations

  • 1 PostEra Inc, 1 Broadway, Cambridge MA 02142, USA.
  • 2 The Wohl Drug Discovery Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • 3 Enamine Ltd., 78 Winston Churchill Street, 02094 Kyiv, Ukraine.
  • 4 Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Virology, Antiviral Drug & Vaccine Research Group, KU Leuven, Leuven, Belgium.
  • 5 MedChemica Consultancy Ltd, Macclesfield, Cheshire, SK11 6DU, UK.
  • 6 Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot OX11 0QX, UK.
  • 7 Centre for Medicines Discovery, University of Oxford, Oxford OX3 7FZ, UK.
  • 8 Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot, UK.
  • 9 Department of Biochemistry, University of Johannesburg, Auckland Park, Johannesburg 2006, South Africa.
PMID: 40667021 DOI: 10.1101/2025.06.19.660642
Abstract

Flaviviruses are a class of pathogenic viruses with pandemic potential which are typically transmitted via infected arthropods. In particular, 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 cellular Antiviral activity, with one example demonstrating excellent murine bioavailability.

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