2. Academic Validation
  3. A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein

A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein

  • Nature. 2025 Apr;640(8058):506-513. doi: 10.1038/s41586-025-08651-6.
Ellen Van Damme 1,  Pravien Abeywickrema # 2,  Yanting Yin # 2,  Jiexiong Xie # 1,  Sofie Jacobs # 1,  Mandeep Kaur Mann 3,  Jordi Doijen 1,  Robyn Miller 2,  Madison Piassek 2,  Simone Marsili 4,  Murali Subramanian 5 6,  Leah Gottlieb 2 7,  Rana Abdelnabi 8 9,  Michiel Van Gool 4,  Nick Van den Broeck 10,  Ines De Pauw 10,  Annick Diels 11,  Peter Vermeulen 11,  Koen Temmerman 11,  Trevor Scobey 12,  Melissa Mattocks 13,  Alexandra Schäfer 12,  Dirk Jochmans 8,  Steven De Jonghe 8,  Pieter Leyssen 8,  Winston Chiu 8,  Mayra Diosa Toro 14 15,  Marleen Zwaagstra 14,  Anouk A Leijs 16,  Heidi L M De Gruyter 16,  Christophe Buyck 17,  Klaas Van Den Heede 1 18,  Frank Jacobs 5,  Christel Van den Eynde 1,  Laura Thijs 10,  Valerie Raeymaekers 10,  Seth Miller 2 19,  Amanda Del Rosario 2,  Johan Neyts 8 9,  Danielle Peeters 11,  Ralph S Baric 12 13,  Frank J M van Kuppeveld 14,  Eric J Snijder 16,  Martijn J van Hemert 16,  Mario Monshouwer 5,  Sujata Sharma 2,  Ruxandra Draghia-Akli 20 21,  Anil Koul 22,  Marnix Van Loock 23
Affiliations

Affiliations

  • 1 Global Public Health R&D, Janssen Pharmaceutica, Beerse, Belgium.
  • 2 Discovery Technologies & Molecular Pharmacology, Janssen Research & Development, Spring House, PA, USA.
  • 3 Global Public Health R&D, Janssen Research & Development, Spring House, PA, USA.
  • 4 Therapeutics Discovery, Janssen-Cilag, Toledo, Spain.
  • 5 Translational PK/PD & Investigative Toxicology (TPPIT), Janssen Research & Development, Beerse, Belgium.
  • 6 Gilead Sciences, Foster City, CA, USA.
  • 7 Red Nucleus, Philadelphia, PA, USA.
  • 8 Virology, Antiviral Drug & Vaccine Research Group, Department of Microbiology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • 9 VirusBank Platform, Leuven, Belgium.
  • 10 Charles River Laboratories, Beerse, Belgium.
  • 11 Discovery Technologies & Molecular Pharmacology, Janssen Research & Development, Beerse, Belgium.
  • 12 Department of Epidemiology, University of North Carolina at Chapel Hill Gillings School of Global Public Health, Chapel Hill, NC, USA.
  • 13 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • 14 Virology Section, Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
  • 15 Eurofins BioPharma Product Testing, Leiden, The Netherlands.
  • 16 Molecular Virology Laboratory, Leiden University Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
  • 17 In Silico Discovery (ISD), Computer-Aided Drug Design (CADD), Janssen Pharmaceutica, Beerse, Belgium.
  • 18 Independent Researcher, Mechelen, Belgium.
  • 19 Spark Therapeutics, Philadelphia, PA, USA.
  • 20 Global Public Health R&D, Janssen Research & Development, Spring House, PA, USA. rdraghia@gmail.com.
  • 21 Research & Development, Novavax Inc., Gaithersburg, MD, USA. rdraghia@gmail.com.
  • 22 Global Public Health R&D, Janssen Pharmaceutica, Beerse, Belgium. anil.koul@lshtm.ac.uk.
  • 23 Global Public Health R&D, Janssen Pharmaceutica, Beerse, Belgium. mvloock@its.jnj.com.
  • # Contributed equally.
PMID: 40140563 DOI: 10.1038/s41586-025-08651-6
Abstract

The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly1,2. Here we describe the identification of JNJ-9676, a small-molecule inhibitor targeting the coronavirus M protein. JNJ-9676 demonstrates in vitro nanomolar Antiviral activity against SARS-CoV-2, SARS-CoV and sarbecovirus strains from bat and pangolin zoonotic origin. Using cryogenic electron microscopy (cryo-EM), we determined a binding pocket of JNJ-9676 formed by the transmembrane domains of the M protein dimer. Compound binding stabilized the M protein dimer in an altered conformational state between its long and short forms, preventing the release of infectious virus. In a pre-exposure Syrian golden hamster model, JNJ-9676 (25 mg per kg twice per day) showed excellent efficacy, illustrated by a significant reduction in viral load and infectious virus in the lung by 3.5 and 4 log10-transformed RNA copies and 50% tissue culture infective dose (TCID50) per mg lung, respectively. Histopathology scores at this dose were reduced to the baseline. In a post-exposure hamster model, JNJ-9676 was efficacious at 75 mg per kg twice per day even when added at 48 h after Infection, when peak viral loads were observed. The M protein is an attractive Antiviral target to block coronavirus replication, and JNJ-9676 represents an interesting chemical series towards identifying clinical candidates addressing the current and future coronavirus pandemics.

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