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

Ellen Damme, Pravien Abeywickrema, Yanting Yin, Jiexiong Xie, Sofie Jacobs, Mandeep Kaur Mann, Jordi Doijen, Robyn Miller, Madison Piassek, Simone Marsili, Murali Subramanian, Leah Gottlieb, Rana Abdelnabi, Michiel Gool, Nick Broeck, Ines Pauw, Annick Diels, Peter Vermeulen, Koen Temmerman, Trevor Scobey, Melissa Mattocks, Alexandra Schäfer, Dirk Jochmans, Steven Jonghe, Pieter Leyssen, Winston Chiu, Mayra Diosa Toro, Marleen Zwaagstra, Anouk A. Leijs, Heidi L. M. Gruyter, Christophe Buyck, Klaas Heede, Frank Jacobs, Christel Eynde, Laura Thijs, Valerie Raeymaekers, Seth Miller, Amanda Rosario, Johan Neyts, Danielle Peeters, Ralph S. Baric, Frank J. M. Kuppeveld, Eric J. Snijder, Martijn J. Hemert, Mario Monshouwer, Sujata Sharma, Ruxandra Draghia-Akli (), Anil Koul () and Marnix Loock ()
Additional contact information
Ellen Damme: Janssen Pharmaceutica
Pravien Abeywickrema: Janssen Research & Development
Yanting Yin: Janssen Research & Development
Jiexiong Xie: Janssen Pharmaceutica
Sofie Jacobs: Janssen Pharmaceutica
Mandeep Kaur Mann: Janssen Research & Development
Jordi Doijen: Janssen Pharmaceutica
Robyn Miller: Janssen Research & Development
Madison Piassek: Janssen Research & Development
Simone Marsili: Janssen-Cilag
Murali Subramanian: Janssen Research & Development
Leah Gottlieb: Janssen Research & Development
Rana Abdelnabi: KU Leuven
Michiel Gool: Janssen-Cilag
Nick Broeck: Charles River Laboratories
Ines Pauw: Charles River Laboratories
Annick Diels: Janssen Research & Development
Peter Vermeulen: Janssen Research & Development
Koen Temmerman: Janssen Research & Development
Trevor Scobey: University of North Carolina at Chapel Hill Gillings School of Global Public Health
Melissa Mattocks: University of North Carolina at Chapel Hill School of Medicine
Alexandra Schäfer: University of North Carolina at Chapel Hill Gillings School of Global Public Health
Dirk Jochmans: KU Leuven
Steven Jonghe: KU Leuven
Pieter Leyssen: KU Leuven
Winston Chiu: KU Leuven
Mayra Diosa Toro: Utrecht University
Marleen Zwaagstra: Utrecht University
Anouk A. Leijs: Leiden University Medical Center
Heidi L. M. Gruyter: Leiden University Medical Center
Christophe Buyck: Janssen Pharmaceutica
Klaas Heede: Janssen Pharmaceutica
Frank Jacobs: Janssen Research & Development
Christel Eynde: Janssen Pharmaceutica
Laura Thijs: Charles River Laboratories
Valerie Raeymaekers: Charles River Laboratories
Seth Miller: Janssen Research & Development
Amanda Rosario: Janssen Research & Development
Johan Neyts: KU Leuven
Danielle Peeters: Janssen Research & Development
Ralph S. Baric: University of North Carolina at Chapel Hill Gillings School of Global Public Health
Frank J. M. Kuppeveld: Utrecht University
Eric J. Snijder: Leiden University Medical Center
Martijn J. Hemert: Leiden University Medical Center
Mario Monshouwer: Janssen Research & Development
Sujata Sharma: Janssen Research & Development
Ruxandra Draghia-Akli: Janssen Research & Development
Anil Koul: Janssen Pharmaceutica
Marnix Loock: Janssen Pharmaceutica

Nature, 2025, vol. 640, issue 8058, 506-513

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-08651-6

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