Discovery and Identification of a Novel Class of Aminopyrimidine Derivatives Specifically Blocking the Interaction between the M and N Structural Proteins of the Coronavirus HCoV-OC43

Abstract The pyrimidine nucleus serves as a key structural motif in drug discovery. Using compound 1 as the lead, we synthesized a series of new aminopyrimidine analogues and assessed their antiviral activity against HCoV-OC43. Among them, compound 13h showed exceptional potency, with an EC50 of 0.12 μM, an SI over 800, and a good safety profile. Systematic mechanistic studies revealed that compound 13h specifically binds to the V201 residue of the M structural protein, disrupting the critical M−N protein interaction required for viral assembly. The V201 site is located precisely at the M−N interaction interface, which accounts for the high potency and safety of 13h. Conclusively, we discovered the first small-molecule inhibitor targeting the M−N binding interface. This novel mechanism of action distinguishes it from existing anti-coronavirus drugs and establishes a promising new antiviral strategy.