Zhang Lei, Xiang Yuhang, Zeng Zhanhao, Peng Bo, Chen Shanshan, Wu Zhenying, Zhong Yiping, Wang Mengya, Zhang Juncheng, Pan Dongli, Yu Yongping, Chen Wenteng
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
School of Pharmacy, Air Force Medical University, Xi'an 710032, China.
J Med Chem. 2025 Jul 10;68(13):13321-13334. doi: 10.1021/acs.jmedchem.4c03034. Epub 2025 Jun 18.
Herpes simplex virus poses a significant public health burden, necessitating the development of alternative therapeutic strategies to combat infection while addressing the growing challenge of drug resistance observed with conventional nucleoside antivirals. Herein, we conducted a mixture-based library screening of an in-house small molecule library, leading to the identification of a novel piperazinone-fused hydroxypyridinone scaffold . Structure-activity relationship studies initiated from hit culminated in the development of lead , which exhibited a significant enhancement in the inhibitory activity against luc-HSV-1. Notably, demonstrated good antiviral efficacy against both acyclovir-sensitive and -resistant HSV strains while showing weak cytotoxicity. Preliminary mechanistic investigations revealed that inhibited viral gene transcription at a very early stage and also inhibited a later stage of viral replication, distinct from acyclovir. Moreover, administration of significantly suppressed viral replication in an HSV-1 strain KOS-infected mouse model with no observable toxicity, offering a promising pathway for further development.
单纯疱疹病毒给公共卫生带来了巨大负担，因此有必要开发替代治疗策略来对抗感染，同时应对传统核苷类抗病毒药物出现的日益严重的耐药性挑战。在此，我们对内部小分子文库进行了基于混合物的文库筛选，从而鉴定出一种新型的哌嗪酮稠合羟基吡啶酮骨架。从活性命中物开始的构效关系研究最终开发出了先导化合物，其对荧光素酶标记的单纯疱疹病毒1型（luc-HSV-1）的抑制活性有显著增强。值得注意的是，该先导化合物对阿昔洛韦敏感和耐药的单纯疱疹病毒株均显示出良好的抗病毒疗效，同时细胞毒性较弱。初步机制研究表明，该先导化合物在病毒基因转录的非常早期阶段就具有抑制作用，并且还能抑制病毒复制的后期阶段，这与阿昔洛韦不同。此外，在单纯疱疹病毒1型KOS株感染的小鼠模型中给予该先导化合物可显著抑制病毒复制，且未观察到毒性，为进一步开发提供了一条有前景的途径。
