Department of Chemistry, Wichita State University, Wichita, Kansas 67260, United States.
Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506, United States.
J Med Chem. 2020 Oct 22;63(20):11945-11963. doi: 10.1021/acs.jmedchem.0c01252. Epub 2020 Oct 2.
Acute gastroenteritis caused by noroviruses has a major impact on public health worldwide in terms of morbidity, mortality, and economic burden. The disease impacts most severely immunocompromised patients, the elderly, and children. The current lack of approved vaccines and small-molecule therapeutics for the treatment and prophylaxis of norovirus infections underscores the need for the development of norovirus-specific drugs. The studies described herein entail the use of the -dimethyl moiety as a means of improving the pharmacological activity and physicochemical properties of a dipeptidyl series of transition state inhibitors of norovirus 3CL protease, an enzyme essential for viral replication. Several compounds were found to be potent inhibitors of the enzyme in biochemical and cell-based assays. The pharmacological activity and cellular permeability of the inhibitors were found to be sensitive to the location of the -dimethyl group.
诺如病毒引起的急性肠胃炎在发病率、死亡率和经济负担方面对全球公共卫生有重大影响。该疾病对免疫功能低下的患者、老年人和儿童的影响最为严重。目前尚无批准的疫苗和小分子疗法用于治疗和预防诺如病毒感染，这凸显了开发诺如病毒特异性药物的必要性。本文所述的研究使用二甲基取代基作为提高一系列二肽基过渡态抑制剂对诺如病毒 3CL 蛋白酶的药理学活性和物理化学性质的手段，该酶是病毒复制所必需的。在生化和基于细胞的测定中，发现几种化合物是该酶的有效抑制剂。抑制剂的药理学活性和细胞通透性对二甲基取代基的位置敏感。
