Li Xin, Wang Yanju, Wu Huan, Wu Shang, Zhao Chunni, Wang Ziming, Song Baoan, Song Runjiang
State Key Laboratory of Green Pesticide, Center for R&D of Fine Chemicals of Guizhou University, Guiyang 550025, China.
State Key Laboratory of Green Pesticide, Center for R&D of Fine Chemicals of Guizhou University, Guiyang 550025, China.
Pestic Biochem Physiol. 2025 Nov;214:106553. doi: 10.1016/j.pestbp.2025.106553. Epub 2025 Jul 8.
Potato virus Y (PVY) is one of the most economically detrimental phytoviruses affecting global Solanaceae, possessing challenges in agrochemical control. The structural elucidation of PVY coat protein (CP) offers opportunities for the rational design of CP-targeted antivirals; however, the feasibility of identifying lead compounds via virtual screening remains largely unexplored. Herein, we report the successful case of structure-based virtual screening leveraging PVY CP, enabling the identification of a structurally novel lead with a unique mechanism of action. Combining quantitative analysis of complex stability and anti-PVY assay allows the determination of molecule 501990 as a promising candidate. 501990 demonstrates exceptional inactivating properties against PVY with EC of 68.80 μg/mL, significantly better than ribavirin (EC = 84.43 μg/mL). Mechanistic studies elucidate the dual interaction of 501990 between PRO126 (P126) and LYS153 (K153) residues on PVY CP. Site-directed mutagenesis along with confocal microscopy observation confirm pathogenesis disruption, as mutant strains (P126A/K153A) exhibit almost loss of intercellular movement and systemic infection capabilities. This study establishes a paradigm for phytoviral protein-based drug discovery, and the identified 501990 may serve as a lead for future virucide developments.
马铃薯Y病毒（PVY）是影响全球茄科植物的最具经济危害性的植物病毒之一，在化学农药防治方面存在挑战。对PVY外壳蛋白（CP）的结构解析为合理设计靶向CP的抗病毒药物提供了机会；然而，通过虚拟筛选鉴定先导化合物的可行性在很大程度上仍未得到探索。在此，我们报告了利用PVY CP进行基于结构的虚拟筛选的成功案例，从而能够鉴定出一种具有独特作用机制的结构新颖的先导化合物。结合对复合物稳定性的定量分析和抗PVY测定，确定分子501990为有前景的候选物。501990对PVY表现出优异的灭活特性，其半数有效浓度（EC）为68.80μg/mL，显著优于利巴韦林（EC = 84.43μg/mL）。机理研究阐明了501990与PVY CP上的PRO126（P126）和LYS153（K153）残基之间的双重相互作用。定点诱变以及共聚焦显微镜观察证实了发病机制的破坏，因为突变株（P126A/K153A）几乎丧失了细胞间移动和系统感染能力。本研究建立了基于植物病毒蛋白的药物发现范式，所鉴定的501990可能作为未来杀病毒剂开发的先导化合物。
