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

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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UNC Libraries
Published
2025-04-02
DOI
https://doi.org/10.17615/kn3r-kp38
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
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article

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

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UNC Libraries
SARS-CoV-2 and COVID-19 Research
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A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein

Amanda Del Rosario, Michiel Van Gool, Peter Vermeulen, Eric J. Snijder, Christel Van den Eynde, Ralph Steven Baric, Pravien Abeywickrema, Danielle Peeters, Steven De Jonghe, Pieter Leyssen, Melissa D. Mattocks, Frank J. M. van Kuppeveld, Frank Jacobs, Christophe Buyck, Yanting Yin, Jiexiong Xie, Sofie Jacobs, Sujata Sharma, Nick Van den Broeck, Heidi L. M. De Gruyter, Rana Abdelnabi, Marnix Van Loock, Mandeep Mann, Annick Diels, Robyn Miller, Ruxandra Draghia‐Akli, Ellen Van Damme, Ines De Pauw, Dirk Jochmans, Mario Monshouwer, Marleen Zwaagstra, Martijn J. van Hemert, Leah Gottlieb, Simone Marsili, Jordi Doijen, Winston Chiu, Klaas Van Den Heede, Alexandra Schäfer, Mayra Diosa Toro, Valerie Raeymaekers, Trevor Scobey, Anouk A. Leijs, Johan Neyts, Koen Temmerman, Madison Piassek, Laura Thijs, Seth Miller, Murali Subramanian, Anil Koul
article en

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.

UNC Libraries
University of North Carolina at Chapel Hill (US)
Openalex Percentile: Top 60%
SARS-CoV-2 and COVID-19 Research
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