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

Area of Science:

• Virology
• Drug Discovery
• Structural Biology

Background:

• The membrane (M) protein is crucial for betacoronavirus assembly and is a conserved viral component.
• Developing inhibitors targeting the M protein presents a viable strategy against coronaviruses.

Purpose of the Study:

• To identify and characterize a novel small-molecule inhibitor targeting the coronavirus M protein.
• To evaluate the antiviral activity and efficacy of the identified inhibitor against SARS-CoV-2 and related viruses.

Main Methods:

• In vitro antiviral assays were performed against various betacoronavirus strains.
• Cryogenic electron microscopy (cryo-EM) was used to determine the binding site and mechanism of action.
• Preclinical efficacy was assessed in Syrian golden hamster models (pre- and post-exposure).

Main Results:

• JNJ-9676 demonstrated nanomolar in vitro antiviral activity against SARS-CoV-2, SARS-CoV, and zoonotic sarbecoviruses.
• Cryo-EM revealed JNJ-9676 binds to the M protein dimer, stabilizing an altered conformation and preventing viral release.
• Significant reduction in viral load and infectious virus in lungs, with normalized histopathology, was observed in hamster models.

Conclusions:

• The coronavirus M protein is a promising target for antiviral development.
• JNJ-9676 is a potent M protein inhibitor with demonstrated efficacy in preclinical models, representing a potential clinical candidate for coronavirus pandemics.