ABSTRACT
The membrane (M) protein of betacoronaviruses is well-conserved and plays a key role in viral assembly. Here, we describe the discovery of JNJ-9676, a novel small molecule targeting the coronaviral (CoV) M protein. JNJ-9676 demonstrates in vitro nanomolar antiviral activity against SARS-CoV2, SARS-CoV, and sarbecovirus strains from bat and pangolin zoonotic origin. Using cryogenic electron microscopy, we determined a novel binding pocket of JNJ-9676 in the M protein's transmembrane domain. Compound binding stabilized the M protein 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/kg BID) showed excellent efficacy illustrated by a significant reduction in viral load and infectious virus in the lung by 3.5 log10 and 4 log10, respectively. Histopathology scores at this dose were reduced to baseline. In a post-exposure hamster model, JNJ-9676 was efficacious at 75mg/kg BID even when added at 48 h post-infection, when peak viral loads were observed. The M protein is an attractive novel antiviral target to block coronavirus replication with JNJ-9676 representing an interesting chemical series towards identifying clinical candidates addressing the current and future CoV pandemics.