2. Academic Validation
  3. Discovery and Preclinical Profile of ALG-097558, a Pan-Coronavirus 3CLpro Inhibitor

Discovery and Preclinical Profile of ALG-097558, a Pan-Coronavirus 3CLpro Inhibitor

  • J Med Chem. 2025 Jul 10;68(13):13436-13454. doi: 10.1021/acs.jmedchem.5c00088.
Dorothée Bardiot 1,  David C McGowan 2,  Kusum Gupta 3,  Jerome Deval 3,  Sandra Chang 3,  Andreas Jekle 3,  Cheng Liu 3,  Sarah Stevens 3,  Vladimir Serebryany 3,  Marcel J Tauchert 4,  Klaus Maskos 4,  Antitsa D Stoycheva 3,  Suping Ren 3,  Ruchika Jaisinghani 3,  Marine O Faucher 3,  Tse-I Lin 2,  Sandro Boland 1,  Patrick Chaltin 5 1,  Arnaud Marchand 1,  Jurgen Wuyts 1,  Steven De Jonghe 6,  Dirk Jochmans 6,  Sreenivasa Anugu 7,  Vamshi Baloju 7,  Kiran Deta 7,  Michael Welch 3,  Pieter Leyssen 6,  Johan Neyts 6 8,  Manon Laporte 6,  Rana Abdelnabi 8,  Haiyang Hu 9,  Peng Zhang 9,  Kha Le 3,  Sushmita Chanda 3,  David B Smith 3,  Pierre Raboisson 2,  Leonid Beigelman 3,  Julian A Symons 3,  Lawrence Blatt 3,  Koen Vandyck 2
Affiliations

Affiliations

  • 1 CISTIM Leuven vzw, Gaston Geenslaan 2, 3001 Leuven, Belgium.
  • 2 Aligos Belgium BV, Gaston Geenslaan 1, 3001 Leuven, Belgium.
  • 3 Aligos Therapeutics, Inc., 1 Corporate Drive, South San Francisco, California 94080, United States.
  • 4 Proteros Biostructures GmbH, Bunsenstr. 7a, 82152 Planegg-Martinsried, Germany.
  • 5 Centre for Drug Design and Discovery (CD3), KU Leuven, Gaston Geenslaan 2, 3001 Leuven, Belgium.
  • 6 Virology, Antiviral Drug & Vaccine Research Group, Department of Microbiology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
  • 7 Aragen Lifesciences Pvt. Ltd, Survey No: 125 & 126, IDA Mallapur, Hyderabad 500076, India.
  • 8 VirusBank Platform, Virology, Antiviral Drug & Vaccine Research Group, Department of Microbiology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
  • 9 Pharmaron, 6 Taihe Road, BDA, Beijing 100176, China.
PMID: 40586480 DOI: 10.1021/acs.jmedchem.5c00088
Abstract

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 (7) 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.

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