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

Damme, E. van; Abeywickrema, P.; Yin, Y.T.; Xie, J.X.; Jacobs, S.; Mann, M.K.; Doijen, J.; Miller, R.; Piassek, M.; Marsili, S.; Subramanian, M.; Gottlieb, L.; Abdelnabi, R.; Gool, M. van; Broeck, N. van den; Pauw, I. de; Diels, A.; Vermeulen, P.; Temmerman, K.; Scobey, T.; Mattocks, M.; Schäfer, A.; Jochmans, D.; Jonghe, S. de; Leyssen, P.; Chiu, W.; Toro, M.D.; Zwaagstra, M.; Leijs, A.A.; Gruyter, H.L.M. de; Buyck, C.; Heede, K. van den; Jacobs, F.; Eynde, C. van den; Thijs, L.; Raeymaekers, V.; Miller, S.; Rosario, A. del; Neyts, J.; Peeters, D.; Baric, R.S.; Kuppeveld, F.J.M. van; Snijder, E.J.; Hemert, M.J. van; Monshouwer, M.; Sharma, S.; Draghia-Akli, R.; Koul, A.; Loock, M. van

doi:doi:10.1038/s41586-025-08651-6

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....Show moreThe 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.Show less

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