tetano
Editor, Senior Moderator
Nature
. 2025 Mar 26.
doi: 10.1038/s41586-025-08651-6. Online ahead of print. A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein
Ellen Van Damme[SUP] 1 [/SUP], Pravien Abeywickrema[SUP] #[/SUP][SUP] 2 [/SUP], Yanting Yin[SUP] #[/SUP][SUP] 2 [/SUP], Jiexiong Xie[SUP] #[/SUP][SUP] 1 [/SUP], Sofie Jacobs[SUP] #[/SUP][SUP] 1 [/SUP], Mandeep Kaur Mann[SUP] 3 [/SUP], Jordi Doijen[SUP] 1 [/SUP], Robyn Miller[SUP] 2 [/SUP], Madison Piassek[SUP] 2 [/SUP], Simone Marsili[SUP] 4 [/SUP], Murali Subramanian[SUP] 5 6 [/SUP], Leah Gottlieb[SUP] 2 7 [/SUP], Rana Abdelnabi[SUP] 8 9 [/SUP], Michiel Van Gool[SUP] 4 [/SUP], Nick Van den Broeck[SUP] 10 [/SUP], Ines De Pauw[SUP] 10 [/SUP], Annick Diels[SUP] 11 [/SUP], Peter Vermeulen[SUP] 11 [/SUP], Koen Temmerman[SUP] 11 [/SUP], Trevor Scobey[SUP] 12 [/SUP], Melissa Mattocks[SUP] 13 [/SUP], Alexandra Schäfer[SUP] 12 [/SUP], Dirk Jochmans[SUP] 8 [/SUP], Steven De Jonghe[SUP] 8 [/SUP], Pieter Leyssen[SUP] 8 [/SUP], Winston Chiu[SUP] 8 [/SUP], Mayra Diosa Toro[SUP] 14 15 [/SUP], Marleen Zwaagstra[SUP] 14 [/SUP], Anouk A Leijs[SUP] 16 [/SUP], Heidi L M De Gruyter[SUP] 16 [/SUP], Christophe Buyck[SUP] 17 [/SUP], Klaas Van Den Heede[SUP] 1 18 [/SUP], Frank Jacobs[SUP] 5 [/SUP], Christel Van den Eynde[SUP] 1 [/SUP], Laura Thijs[SUP] 10 [/SUP], Valerie Raeymaekers[SUP] 10 [/SUP], Seth Miller[SUP] 2 19 [/SUP], Amanda Del Rosario[SUP] 2 [/SUP], Johan Neyts[SUP] 8 9 [/SUP], Danielle Peeters[SUP] 11 [/SUP], Ralph S Baric[SUP] 12 13 [/SUP], Frank J M van Kuppeveld[SUP] 14 [/SUP], Eric J Snijder[SUP] 16 [/SUP], Martijn J van Hemert[SUP] 16 [/SUP], Mario Monshouwer[SUP] 5 [/SUP], Sujata Sharma[SUP] 2 [/SUP], Ruxandra Draghia-Akli[SUP] 20 21 [/SUP], Anil Koul[SUP] 22 [/SUP], Marnix Van Loock[SUP] 23 [/SUP]
Affiliations
The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly[SUP]1,2[/SUP]. 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[SUB]10[/SUB]-transformed RNA copies and 50% tissue culture infective dose (TCID[SUB]50[/SUB]) 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.
. 2025 Mar 26.
doi: 10.1038/s41586-025-08651-6. Online ahead of print. A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein
Ellen Van Damme[SUP] 1 [/SUP], Pravien Abeywickrema[SUP] #[/SUP][SUP] 2 [/SUP], Yanting Yin[SUP] #[/SUP][SUP] 2 [/SUP], Jiexiong Xie[SUP] #[/SUP][SUP] 1 [/SUP], Sofie Jacobs[SUP] #[/SUP][SUP] 1 [/SUP], Mandeep Kaur Mann[SUP] 3 [/SUP], Jordi Doijen[SUP] 1 [/SUP], Robyn Miller[SUP] 2 [/SUP], Madison Piassek[SUP] 2 [/SUP], Simone Marsili[SUP] 4 [/SUP], Murali Subramanian[SUP] 5 6 [/SUP], Leah Gottlieb[SUP] 2 7 [/SUP], Rana Abdelnabi[SUP] 8 9 [/SUP], Michiel Van Gool[SUP] 4 [/SUP], Nick Van den Broeck[SUP] 10 [/SUP], Ines De Pauw[SUP] 10 [/SUP], Annick Diels[SUP] 11 [/SUP], Peter Vermeulen[SUP] 11 [/SUP], Koen Temmerman[SUP] 11 [/SUP], Trevor Scobey[SUP] 12 [/SUP], Melissa Mattocks[SUP] 13 [/SUP], Alexandra Schäfer[SUP] 12 [/SUP], Dirk Jochmans[SUP] 8 [/SUP], Steven De Jonghe[SUP] 8 [/SUP], Pieter Leyssen[SUP] 8 [/SUP], Winston Chiu[SUP] 8 [/SUP], Mayra Diosa Toro[SUP] 14 15 [/SUP], Marleen Zwaagstra[SUP] 14 [/SUP], Anouk A Leijs[SUP] 16 [/SUP], Heidi L M De Gruyter[SUP] 16 [/SUP], Christophe Buyck[SUP] 17 [/SUP], Klaas Van Den Heede[SUP] 1 18 [/SUP], Frank Jacobs[SUP] 5 [/SUP], Christel Van den Eynde[SUP] 1 [/SUP], Laura Thijs[SUP] 10 [/SUP], Valerie Raeymaekers[SUP] 10 [/SUP], Seth Miller[SUP] 2 19 [/SUP], Amanda Del Rosario[SUP] 2 [/SUP], Johan Neyts[SUP] 8 9 [/SUP], Danielle Peeters[SUP] 11 [/SUP], Ralph S Baric[SUP] 12 13 [/SUP], Frank J M van Kuppeveld[SUP] 14 [/SUP], Eric J Snijder[SUP] 16 [/SUP], Martijn J van Hemert[SUP] 16 [/SUP], Mario Monshouwer[SUP] 5 [/SUP], Sujata Sharma[SUP] 2 [/SUP], Ruxandra Draghia-Akli[SUP] 20 21 [/SUP], Anil Koul[SUP] 22 [/SUP], Marnix Van Loock[SUP] 23 [/SUP]
Affiliations
- PMID: 40140563
- DOI: 10.1038/s41586-025-08651-6
The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly[SUP]1,2[/SUP]. 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[SUB]10[/SUB]-transformed RNA copies and 50% tissue culture infective dose (TCID[SUB]50[/SUB]) 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.