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

Ellen Van 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 Van Gool; Nick Van den Broeck; Ines De Pauw; Annick Diels; Peter Vermeulen; Koen Temmerman; Trevor Scobey; Melissa Mattocks; Alexandra Schäfer; Dirk Jochmans; Steven De Jonghe; Pieter Leyssen; Winston Chiu; Mayra Diosa Toro; Marleen Zwaagstra; Anouk A Leijs; Heidi L M De Gruyter; Christophe Buyck; Klaas Van Den Heede; Frank Jacobs; Christel Van den Eynde; Laura Thijs; Valerie Raeymaekers; Seth Miller; Amanda Del Rosario; Johan Neyts; Danielle Peeters; Ralph S Baric; Frank J M van Kuppeveld; Eric J Snijder; Martijn J van Hemert; Mario Monshouwer; Sujata Sharma; Ruxandra Draghia-Akli; Anil Koul; Marnix Van Loock

doi:10.1038/s41586-025-08651-6

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

Ellen Van 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 Van Gool
, Nick Van den Broeck
, Ines De Pauw
, Annick Diels
, Peter Vermeulen
, Koen Temmerman
, Trevor Scobey

Melissa Mattocks, Alexandra Schäfer, Dirk Jochmans, Steven De Jonghe, Pieter Leyssen, Winston Chiu, Mayra Diosa Toro, Marleen Zwaagstra, Anouk A Leijs, Heidi L M De Gruyter, Christophe Buyck, Klaas Van Den Heede, Frank Jacobs, Christel Van den Eynde, Laura Thijs, Valerie Raeymaekers, Seth Miller, Amanda Del Rosario, Johan Neyts, Danielle Peeters, Ralph S Baric, Frank J M van Kuppeveld, Eric J Snijder, Martijn J van Hemert, Mario Monshouwer, Sujata Sharma, Ruxandra Draghia-Akli^*, Anil Koul^*, Marnix Van Loock^*

^*Corresponding author for this work

Gillings School of Global Public Health
Janssen Research & Development, Beerse, Belgium
Therapeutics Discovery
Rega Institute for Medical Research
Charles River Laboratories
University of North Carolina at Chapel Hill Gillings School of Global Public Health
University of North Carolina School of Medicine at Chapel Hill
Leiden University Medical Center
In Silico Discovery (ISD)

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly 1,2. 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 log 10-transformed RNA copies and 50% tissue culture infective dose (TCID 50) 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.

Original language	English
Pages (from-to)	506–513
Number of pages	8
Journal	Nature
Volume	640
Issue number	8058
Early online date	26 Mar 2025
DOIs	https://doi.org/10.1038/s41586-025-08651-6
Publication status	Published - 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

Funding

We thank K. Vercauteren and A.-T. Henze (Akkodis Belgium) for medical writing and coordination support on behalf of Janssen Pharmaceutica; L. Vijgen, M. Burcin, L. Zhang, E. Parmee and L. Lombardo for the comments and discussions; B. C. Arquero for the analysis of the NMR spectra of JNJ-9676; and M. Van Heerden for the histopathology scoring. This work was supported by Janssen Research & Development. This project has also been funded in part with federal funds from the Office of the Administration for Strategic Preparedness and Response, Biomedical Advanced Research and Development Authority (BARDA), under OTA numbers HHSO100201700018C and HHSO100201800012C. The panCoV nLUC drug assays were developed under NIH AID AI171292 (RSB) and applied to this project. M.V.L., E.V.D., M.V.G. and C.B. are named as inventors on a pending patent application claiming inhibitors of coronavirus (WO 2024/008909), which was filed by the Applicant Janssen Pharmaceutica. M.V.L., E.V.D., J.X., S.J., L.G., J.D., M.V.G., R.D.-A., A.D., S. Marsili, S. Miller, C.V.d.E., A.D.R., P.V., K.T., D.P. and C.B. were/are employees of Janssen Pharmaceutica and may possess stocks of Johnson & Johnson. S. Miller is an employee of Spark Therapeutics and may possess stocks of Roche. N.V.d.B., L.T., V.R. and I.D.P. are employees of Charles River Laboratories, a contract research organization and may possess stocks of Johnson & Johnson. M.S. is an employee of Gilead Sciences and may possess stocks of Gilead Sciences. A.A.L., H.L.M.d.G., E.J.S. and M.J.v.H. received funding from Janssen Pharmaceutica to perform contract research. M.D.T., M.Z. and F.J.M.v.K. received funding from Janssen Pharmaceutica to perform contract research. The other authors declare no competing interests.

Funders	Funder number
Administration for Strategic Preparedness and Response
Janssen Research and Development
Janssen Pharmaceutica
Biomedical Advanced Research and Development Authority	HHSO100201800012C, HHSO100201700018C

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Van Damme, E., Abeywickrema, P., Yin, Y., Xie, J., Jacobs, S., Mann, M. K., Doijen, J., Miller, R., Piassek, M., Marsili, S., Subramanian, M., Gottlieb, L., Abdelnabi, R., Van Gool, M., Van den Broeck, N., De Pauw, I., Diels, A., Vermeulen, P., Temmerman, K., ... Van Loock, M. (2025). A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein. Nature, 640(8058), 506–513. https://doi.org/10.1038/s41586-025-08651-6

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title = "A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein",

abstract = "The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly 1,2. 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 log 10-transformed RNA copies and 50\% tissue culture infective dose (TCID 50) 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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year = "2025",

doi = "10.1038/s41586-025-08651-6",

language = "English",

volume = "640",

pages = "506–513",

journal = "Nature",

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Van Damme, E, Abeywickrema, P, Yin, Y, Xie, J, Jacobs, S, Mann, MK, Doijen, J, Miller, R, Piassek, M, Marsili, S, Subramanian, M, Gottlieb, L, Abdelnabi, R, Van Gool, M, Van den Broeck, N, De Pauw, I, Diels, A, Vermeulen, P, Temmerman, K, Scobey, T, Mattocks, M, Schäfer, A, Jochmans, D, De Jonghe, S, Leyssen, P, Chiu, W, Diosa Toro, M, Zwaagstra, M, Leijs, AA, De Gruyter, HLM, Buyck, C, Van Den Heede, K, Jacobs, F, Van den Eynde, C, Thijs, L, Raeymaekers, V, Miller, S, Del Rosario, A, Neyts, J, Peeters, D, Baric, RS, van Kuppeveld, FJM, Snijder, EJ, van Hemert, MJ, Monshouwer, M, Sharma, S, Draghia-Akli, R, Koul, A & Van Loock, M 2025, 'A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein', Nature, vol. 640, no. 8058, pp. 506–513. https://doi.org/10.1038/s41586-025-08651-6

TY - JOUR

T1 - A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein

AU - Van Damme, Ellen

AU - Abeywickrema, Pravien

AU - Yin, Yanting

AU - Xie, Jiexiong

AU - Jacobs, Sofie

AU - Mann, Mandeep Kaur

AU - Doijen, Jordi

AU - Miller, Robyn

AU - Piassek, Madison

AU - Marsili, Simone

AU - Subramanian, Murali

AU - Gottlieb, Leah

AU - Abdelnabi, Rana

AU - Van Gool, Michiel

AU - Van den Broeck, Nick

AU - De Pauw, Ines

AU - Diels, Annick

AU - Vermeulen, Peter

AU - Temmerman, Koen

AU - Scobey, Trevor

AU - Mattocks, Melissa

AU - Schäfer, Alexandra

AU - Jochmans, Dirk

AU - De Jonghe, Steven

AU - Leyssen, Pieter

AU - Chiu, Winston

AU - Diosa Toro, Mayra

AU - Zwaagstra, Marleen

AU - Leijs, Anouk A

AU - De Gruyter, Heidi L M

AU - Buyck, Christophe

AU - Van Den Heede, Klaas

AU - Jacobs, Frank

AU - Van den Eynde, Christel

AU - Thijs, Laura

AU - Raeymaekers, Valerie

AU - Miller, Seth

AU - Del Rosario, Amanda

AU - Neyts, Johan

AU - Peeters, Danielle

AU - Baric, Ralph S

AU - van Kuppeveld, Frank J M

AU - Snijder, Eric J

AU - van Hemert, Martijn J

AU - Monshouwer, Mario

AU - Sharma, Sujata

AU - Draghia-Akli, Ruxandra

AU - Koul, Anil

AU - Van Loock, Marnix

PY - 2025

Y1 - 2025

N2 - The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly 1,2. 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 log 10-transformed RNA copies and 50% tissue culture infective dose (TCID 50) 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.

AB - The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly 1,2. 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 log 10-transformed RNA copies and 50% tissue culture infective dose (TCID 50) 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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U2 - 10.1038/s41586-025-08651-6

DO - 10.1038/s41586-025-08651-6

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SN - 0028-0836

VL - 640

SP - 506

EP - 513

JO - Nature

JF - Nature

IS - 8058

ER -

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

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