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
Yue Gong, Zhihui Yu, Runze Meng, Xican Ma, Jianrui Li, Qionglu Duan, Hongxuan Li, Jingyang Zhu, Yanhong Li, Xinyi Li, Yanan Ni, Yinghong Li, Yonghua Liu, Zonggen Peng, Danqing SongAbstract
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.