Hit to Lead Optimization of Non-Peptidic Inhibitors of Alphaviral Cysteine Protease

项目摘要 由蚊媒甲型病毒引起的新病毒感染，如委内瑞拉/西方- 欧洲东部马脑炎病毒(VEEV、EEEV或WeEV)和基孔肯雅病毒迫在眉睫- 对世界各地公共卫生系统的威胁。没有疫苗或治疗AP- 已被证实用于人类对抗甲型病毒，我们对这种分子的了解有限 大多数甲型病毒的致病性。如果甲型病毒感染的地区性或跨国爆发 在未来发生的情况下，可以将生命损失和经济生产力损失降至最低或防止 如果有治疗性或预防性药物的话。在本申请中，我们建议调查- 转化为一系列新的分子，抑制非结构蛋白的蛋白酶域 VEEV的2(NsP2)，阻断VEEV在人细胞中的复制，并服从于系统性 对药物开发至关重要的结构性变化。该项目的主要目标是：(A)。 用多参数研究nsP2的共价可逆和机理可逆抑制剂 结构-活性研究关系(SAR)研究以及互补代谢和 生物利用度研究；及(B)。研究分子间的分子相互作用 和nsP2，使用结晶学和分子模拟，这将促进靶向特异的操作。 对候选药物进行时效化。项目目标将有助于推动COM- Pound系列作为一流的nsP2抑制剂进行临床前研究 在生理相关浓度下的甲型病毒活性。此外，这些分子将 也可以作为有价值的分子工具，促进我们对nsP2在 甲型病毒的致病性。

Project Summary Emerging viral infections caused by mosquito-borne alphaviruses such as Venezuelan/West- ern/Eastern equine encephalitis virus (VEEV, EEEV or WEEV) and Chikungunya virus are loom- ing threats to public health systems around the world. There are no vaccines or therapeutics ap- proved for human use against alphaviruses, and we have limited understanding of the molecular pathogenicity of most alphaviruses. If regional or transnational outbreak of alphavirus infections occur in the future, loss of life and loss of economic productivity can be minimized or prevented if therapeutic or prophylactic agents are available. In this application, we propose an investiga- tion into a new series of molecules that inhibit the protease domain of the non-structural protein 2 (nsP2) of VEEV, blocks the replication of VEEV in human cells, and are amenable to systematic structural changes that is important for drug development. The main goals of this project are: (a). To investigate covalent and mechanism-based reversible inhibitors of nsP2 using multiparameter structure-activity studies relationships (SAR) studies along with complementary metabolic and bioavailability studies; and (b). To investigate the molecular interactions between the molecules and nsP2 using crystallography and molecular modelling, which will facilitate target-specific op- timization of drug lead candidates. The project goals will facilitate the advancement of the com- pound series towards preclinical investigation as first-in-class nsP2 inhibitors that have anti-al- phaviral activities at physiologically relevant concentrations. Additionally, the molecules will also serve as valuable molecular tools to advance our understanding of the role of nsP2 in the pathogenicity of alphaviruses.