A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Van Damme Ellen, Abeywickrema Pravien, Yin Yanting, Xie Jiexiong, Jacobs Sofie, Mann Mandeep Kaur, Doijen Jordi, Miller Robyn, Piassek Madison, Marsili Simone, Subramanian Murali, Gottlieb Leah, Abdelnabi Rana, Van Gool Michiel, Van den Broeck Nick, De Pauw Ines, Diels Annick, Vermeulen Peter, Temmerman Koen, Scobey Trevor, Mattocks Melissa, Schäfer Alexandra, Jochmans Dirk, De Jonghe Steven, Leyssen Pieter, Chiu Winston, Diosa Toro Mayra, Zwaagstra Marleen, Leijs Anouk A, De Gruyter Heidi L M, Buyck Christophe, Van Den Heede Klaas, Jacobs Frank, Van den Eynde Christel, Thijs Laura, Raeymaekers Valerie, Miller Seth, Del Rosario Amanda, Neyts Johan, Peeters Danielle, Baric Ralph S, van Kuppeveld Frank J M, Snijder Eric J, van Hemert Martijn J, Monshouwer Mario, Sharma Sujata, Draghia-Akli Ruxandra, Koul Anil, Van Loock Marnix
Аннотация
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.