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
  • 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. [email protected].
  • 21. Research & Development, Novavax Inc., Gaithersburg, MD, USA. [email protected].
  • 22. Global Public Health R&D, Janssen Pharmaceutica, Beerse, Belgium. [email protected].
  • 23. Global Public Health R&D, Janssen Pharmaceutica, Beerse, Belgium. [email protected].
  • # 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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