Discovery and Preclinical Profile of ALG-097558, a Pan-Coronavirus 3CLpro Inhibitor
The SARS-CoV-2 outbreak of 2019 had a devastating impact on global health and economies worldwide. The viral cysteine protease (3CLpro) is responsible for viral polypeptide bond cleavages and is therefore an essential target to inhibit viral replication. Here, we report the discovery of an orally available, reversible covalent inhibitor of the SARS-CoV-2 main protease that is also highly active across other human coronaviruses and demonstrated oral efficacy in a Syrian hamster infection model at low plasma concentrations. Projection of pharmacokinetics (PK) in humans, based on PK studies in preclinical species and enhanced in vitro/in vivo efficacy of ALG-097558 (<b>7</b>) indicated the potential for BID dosing without the need for ritonavir, the PK boosting component of Paxlovid. After preclinical safety and pharmacological studies, ALG-097558 has progressed to phase 1 clinical trials.
Authors
- Lawrence M. Blatt (ORCID: https://orcid.org/0000-0002-6442-9207)
- Tse‐I Lin
- Sandro Boland (ORCID: https://orcid.org/0000-0001-5819-8273)
- Marcel J Tauchert (ORCID: https://orcid.org/0000-0002-2571-7687)
- Vladimir Serebryany
- Patrick Chaltin (ORCID: https://orcid.org/0000-0001-6692-5004)
- Dorothée Bardiot
- Mary Ann Faucher (ORCID: https://orcid.org/0000-0002-8353-3077)
- Steven De Jonghe (ORCID: https://orcid.org/0000-0002-3872-6558)
- Antitsa Stoycheva (ORCID: https://orcid.org/0000-0003-1907-0319)
- Peng Zhang (ORCID: https://orcid.org/0000-0002-4137-8267)
- Pieter Leyssen (ORCID: https://orcid.org/0000-0002-7537-1688)
- Ruchika Jaisinghani
- Sarah Stevens (ORCID: https://orcid.org/0000-0003-1461-2860)
- Arnaud Marchand (ORCID: https://orcid.org/0000-0002-0007-382X)
- David C. McGowan (ORCID: https://orcid.org/0000-0002-3759-6771)
- Pierre Raboisson
- Andreas Jekle (ORCID: https://orcid.org/0000-0001-9416-2622)
- Sandra P. Chang (ORCID: https://orcid.org/0000-0002-8535-964X)
- Hai Hu (ORCID: https://orcid.org/0000-0002-5348-5641)
- Sushmita Chanda
- Rana Abdelnabi (ORCID: https://orcid.org/0000-0001-9771-7312)
- K. Maskos
- Michael J. Welch (ORCID: https://orcid.org/0000-0001-7868-5079)
- Kha Le (ORCID: https://orcid.org/0000-0002-5446-819X)
- Dirk Jochmans (ORCID: https://orcid.org/0000-0002-9265-6028)
- Julian Symons
- Koen Vandyck (ORCID: https://orcid.org/0000-0002-0923-8301)
- Johan Neyts (ORCID: https://orcid.org/0000-0002-0033-7514)
- Manon Laporte (ORCID: https://orcid.org/0000-0001-5708-1321)
- Liu C (ORCID: https://orcid.org/0000-0002-2219-1018)
- Jérôme Deval (ORCID: https://orcid.org/0000-0002-0133-4673)
- Suping Ren (ORCID: https://orcid.org/0009-0009-7179-0242)
- David B. Smith (ORCID: https://orcid.org/0000-0002-4970-6894)
- Kusum Gupta (ORCID: https://orcid.org/0000-0002-6427-5404)
- Leonid Beigelman
- Sreenivasa Anugu
- Jurgen Wuyts
- Vamshi Baloju
- Kiran Deta
Institutions
- Rega Institute for Medical Research (BE)
- KU Leuven (BE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-06-30
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00088
- Citations
- 1
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- National Institute of Allergy and Infectious Diseases