SARS-CoV-2 protease inhibitors for treating COVID-19

摘要 这个项目的主要目标是推进我们广泛的初步成果和发展 有效治疗新冠肺炎的新型蛋白酶抑制剂药物。新冠肺炎大流行， 由高度传染性的严重急性呼吸综合征冠状病毒2型(SARS-CoV- 2)，于2019年12月出现在中国位于中部的湖北省武汉市。疫情的爆发已经 以惊人的速度蔓延，造成了一场灾难性的全球健康危机，世界上类似的 已经有100多年没见过了。SARS-CoV-2病毒已经蔓延到周围的几乎每一个大洲 该病毒在全球范围内传播，影响了480多万人，导致380 000多人死亡。到目前为止， 目前还没有针对新冠肺炎的疫苗或经批准的有效药物治疗方法。最新进展 开发抗病毒药物是减少世界各地发病率和死亡率的首要任务。 SARS-CoV-2编码两类半胱氨酸蛋白酶--3-类糜蛋白酶 (3CLPRO)和类木瓜蛋白酶(PLPRO)，这是冠状病毒复制的关键。 这两种蛋白水解酶已被公认为抗肿瘤药物开发的重要靶点。 新冠肺炎及相关致病冠状病毒。 在我们对抗SARS和MERS冠状病毒的广泛合作工作中，我们之前 开发并报道了各种共价和非共价小分子- 具有显著抗病毒活性的SARS-CoV-3CLPro分子可逆抑制剂。我们 也证明了PLPro是一个重要的药物靶点，通过开发第一个非共价， 在细胞内显示有效抗病毒活性的可逆和有效的SARS-CoV-PLPro抑制剂 在文化和动物模型中。我们进行了结构活性和广泛的X射线结构 对SARS、MERS和PERS的3CLPro和PLPRO活性部位的分子研究 最近一次是SARS-CoV-2。此外，我们现在已经产生了一些新的小型 SARS-CoV-2、3CLPro和PLPro的分子铅抑制物，并测定了几种高活性的 SARS-CoV-2 3CLPro抑制剂复合体的分辨X射线结构这项工作构成了 我们提议的研究。我们现在计划设计、优化和开发结构新颖的药物- 显示出良好的药理特性和低的 毒性。我们将开展一项多学科的研究工作，将X射线结构- 指导设计、迭代药物化学、分子建模、生物化学和生物物理学 检测、抗病毒和细胞生物学研究与各种理化检测相结合 针对新冠肺炎的临床前开发优化化合物。

Abstract The main objective of this project is to advance our extensive preliminary results and develop novel protease inhibitor drugs for the effective treatment of COVID-19. The COVID-19 pandemic, caused by the highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2), emerged in central China's Hubei Province, Wuhan in December 2019. The outbreak has spread at an alarming rate, creating a catastrophic global health crisis the likes of which the world has not witnessed in over 100 years. SARS-CoV-2 has spread to nearly every continent around the globe and has affected over 4.8 million individuals with more than 380,000 deaths. Thus far, there are no vaccines or approved effective drug treatments against COVID-19. The development of antiviral agents is the foremost priority for reducing morbidity and mortality around the world. SARS-CoV-2 encodes two classes of cysteine proteases, the 3-chymotrypsin-like protease (3CLpro) and the papain-like protease (PLpro), which are critical for coronavirus replication. These two proteases have been recognized as important targets for drug development against COVID-19 and related pathogenic coronaviruses. In our extensive collaborative work against SARS and MERS coronaviruses, we previously developed and reported the development of a variety of covalent and non-covalent small- molecule reversible inhibitors of SARS-CoV-3CLpro that showed significant antiviral activity. We also demonstrated that PLpro is a significant drug target by developing the first non-covalent, reversible and potent inhibitors of SARS-CoV-PLpro that show effective antiviral activity in cell culture and in an animal model. We carried out structure-activity and extensive X-ray structural studies to gain molecular insight into the 3CLpro and PLpro active sites of SARS, MERS and most recently SARS-CoV-2. Furthermore, we have now generated a number of new small molecule lead inhibitors of SARS-CoV-2 3CLpro and PLpro and determined several high- resolution X-ray structures of SARS-CoV-2 3CLpro inhibitor complexes. This work forms the basis of our proposed studies. We now plan to design, optimize and develop structurally novel drug- like and broad-spectrum protease inhibitors that show favorable pharmacological profiles and low toxicity. We will carry out a multidisciplinary research effort that will integrate X-ray structure- guided design, iterative medicinal chemistry, molecular modeling, biochemical and biophysical assays, antivirus and cell biological studies in combination with various physiochemical assays to optimize compounds for preclinical development against COVID-19.