Yinghong Li

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.

The recurrent mpox outbreak has raised widespread global concern, yet specific antiviral therapies remain unavailable. Based on the α, β-unsaturated acrylamide covalent warhead of tranilast (TRA), we designed and synthesized 24 new TRA derivatives and evaluated their anti-orthopoxvirus activity using a VTT-Fluc assay. Compound 8l exhibited the most potent antipoxvirus activity and moderate activity against monkeypox clade IIb, with EC₅₀ values of 6.1 and 47.1 μM, respectively, significantly outperformed TRA. In a VTT-Fluc nude mouse model, oral administration of 8l at 90 mg/kg achieved an 88.2% viral inhibition rate. Mechanistic studies revealed 8l exerted dual-target inhibition by acting on viral A17L and mRNA methyltransferase, thereby blocking membrane fusion and intracellular biosynthesis. The acrylamide warhead in 8l forms covalent adducts with serine residues of both targets via Michael addition. This work provides a promising covalent lead and identifies potential targets for the development of broad-spectrum anti-orthopoxvirus agents.

Aloperine derivatives can promote the degradation of PD-L1 through different pathways and exert antitumor immunity, but their direct targets remain unclear. In this study, 30 aloperine derivatives were synthesized and screened for their efficacy in reducing PD-L1 levels, and compound 7a was found to effectively promote PD-L1 degradation through the lysosomal pathway. Then, based on the DTAGen deep learning model, lysosome-associated membrane protein 2 (LAMP2) was predicted to be a potential functional target of 7a. Multiple biochemical assays demonstrated that 7ainduced PD-L1 degradation through the LAMP2-mediated lysosomal pathway, with a KD value of 5.58 µM. Furthermore, molecular dynamics simulations elucidated that 7a promoted the compactness of the N-terminal domain of LAMP2, making it easier to form high-order oligomers, thereby accelerating PD-L1 degradation. Therefore, the computational (dry) and experimental (wet) data fusion strategy efficiently identified LAMP2 as the direct target of 7a for the degradation of PD-L1 via lysosomal pathway, providing a reference case for the rapid discovery of target.