Novel small-molecule inhibitors of SARS-CoV-2 protease

这个项目的总体目标是使用药物化学、X射线结晶学、 生物化学和生物活性检测以开发有效的、类药物的猪瘟病毒主要蛋白酶(MPRO)抑制剂 SARS-CoV-2(SARS-2)是一种新型冠状病毒，可引起严重肺部疾病COVID的爆发。 19(2019年冠状病毒病)。SARS-2在武汉、中国等地出现，并很快蔓延到210个国家 全世界。世卫组织已于2020年3月11日宣布新冠肺炎为全球大流行。截至6月初，SARS-2已经 全球约有700万人(确诊病例)感染，其中包括美国约200万例。这些数字是 每天都在快速增长。SARS-2具有很强的传染性。而大多数感染SARS-2的患者(81%)表现出 症状相对较轻，危及生命的严重疾病，包括严重肺炎、败血症和器官衰竭， 对于年龄在≥65岁的人和患有严重潜在疾病的人来说，发生这种疾病的风险明显更高 医疗条件。SARS-2已在全球造成约40万人死亡，其中包括美国的11万人(截至年初 2020年6月)，这使它成为现代史上最危险的病原体之一。因此，有一种 迫切需要为SARS-2感染找到有效的治疗方法和疫苗。主要的蛋白水解酶(MPRO) SARS-2对于病毒复制是必不可少的，因此是药物靶标。具体目标1是使用日粮抑制剂 设计、药物化学和构效关系(SAR)研究以寻找更有效的抑制剂 SARS-2 MPRO。具体目标2是进行酶抑制、X射线结晶学和其他 生化/物理研究，以表征目标1中制造的化合物，这将用于指导Rational 目标1中的设计和SAR研究，以寻找具有更高效力的化合物。具体目标3是执行 选择SARS-2 MPRO有效抑制剂的细胞毒性和细胞抗病毒活性测试，以便找到 无细胞毒性，有效的抗病毒化合物，可对抗SARS-2和SARS-1感染。这一试点项目的成功将 导致具有更强效力的小分子抑制剂，可以强烈地抑制SARS-2复制。在……里面 此外，X射线结晶学和其他生化/物理研究将揭示抑制剂-MPRO 互动。这些化合物将成为进一步药物开发的新的药理先导。 针对SARS-2和其他冠状病毒感染。

The overall objective of this project is to use a combination of medicinal chemistry, X-ray crystallography, biochemical and biological activity testing to develop potent, drug-like inhibitors of the main protease (Mpro) of SARS-CoV-2 (SARS-2), a novel coronavirus that causes an outbreak of a serious pulmonary disease COVID- 19 (coronavirus disease 2019). SARS-2 has emerged in Wuhan, China and soon spread to >210 countries worldwide. WHO has declared COVID-19 a global pandemic in March 11, 2020. As of early June, SARS-2 has infected ~7 million people (confirmed cases) globally, including ~2 million cases in the US. These numbers are rapidly growing everyday. SARS-2 is highly contagious. While most patients (81%) infected with SARS-2 show relatively mild symptoms, life-threatening severe illness, including severe pneumonia, sepsis and organ failure, can occur at a significantly higher risk for people at age of ≥65 years and people with serious underlying medical conditions. SARS-2 has caused ~400,000 deaths globally including >110,000 in the US (as of early June, 2020), which makes it one of the most dangerous pathogens in modern history. There is therefore a pressing need to find effective therapeutics and vaccines for SARS-2 infection. The main protease (Mpro) of SARS-2 is essential for the viral replication and therefore a drug target. Specific Aim 1 is to use ration inhibitor design, medicinal chemistry and structure-activity relationship (SAR) studies to find more potent inhibitors of SARS-2 Mpro. Specific Aim 2 is to perform enzyme inhibition, X-ray crystallographic and other biochemical/physical studies to characterize compounds made in Aim 1, which will be used to guide rational design and SAR studies in Aim 1 to find compounds with improved potency. Specific Aim 3 is to perform cytotoxicity and cellular antiviral activity testing of selected potent inhibitors of SARS-2 Mpro, in order to find non-cytotoxic, potent antiviral compound against SARS-2 and -1 infections. Success of this pilot project would lead to small-molecule inhibitors with improved potency that can strongly inhibit SARS-2 replication. In addition, X-ray crystallography and other biochemical/physical studies would reveal the inhibitor-Mpro interactions. These compounds would serve as novel pharmacological leads for further drug development targeting SARS-2 and other coronavirus infection.