A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein
Abstract
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.
Article Details
Authors (49)
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