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bioRxiv2025June 17, 2025Journal Article

Open-science discovery of DNDI-6510, a compound that addresses genotoxic and metabolic liabilities of the COVID Moonshot SARS-CoV-2 Mpro lead inhibitor.

Ed J Griffen1, Daren Fearon2,3, Briana L McGovern4,5, Lizbe Koekemoer6, Blake H Balcomb2,3, Tamas Szommer6, Gwendolyn Fate7, Ralph P Robinson7, Bruce A Lefker7, Shirly Duberstein8, Noa Lahav8, , Stephanie Braillard9, Laura Vangeel10, Manon Laporte10, Fabienne Burgat Charvillon9, A Kenneth MacLeod11, Andrew Wells12, Pauline Garner13, Richard Knight13, Paul Rees14, Anthony Simon9, Dirk Jochmans10, Johan Neyts10, Kevin D Read11, Haim Barr8, Matthew Robinson15, Alpha Lee15, Nir London16, John Chodera17, Frank von Delft6,2,18,3, Kris M White4,5, Ben Perry9, Peter Sjö9, Annette von Delft6
1MedChemica Consultancy Ltd, Motorworks, Chestergate, Macclesfield, SK11 6GU, UK.
2Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, UK.
3Research complex at Harwell. Harwell Science and Innovation Campus, Didcot, UK.
4Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
7Thames Pharma Partners LLC, Mystic, Connecticut, USA.
8G-INCPM, Weizmann Institute of Science, Rechovot, Israel.
9Drugs for Neglected Diseases initiative, Geneva, Switzerland.
10Virology, Antiviral Drug & Vaccine Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.
11Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
12Charnwood Technical Consulting, UK.
13ApconiX, Mereside, Alderley Park, Cheshire, UK.
14Compass Business Partners Ltd, Gerrards Cross, UK.
15PostEra Inc., Cambridge, MA 02142, USA.
16Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel.
17Program in Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
18Department of Biochemistry, University of Johannesburg, Auckland Park, Johannesburg 2006, South Africa.
PubMed PMC DOI PDF

Abstract

The 2020 SARS-CoV-2 coronavirus pandemic highlighted the urgent need for novel small molecule antiviral drugs. (S)-x38 DNDI-6510 is a non-covalent SARS-CoV-2 main protease inhibitor developed by the open science collaboration COVID Moonshot. Here, we report on the metabolic and toxicologic optimization of the lead series previously disclosed by the COVID Moonshot Initiative, leading up to the sele…

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