Broad-spectrum therapeutics against SARS-CoV-2 3CL protease

项目总结/摘要 COVID-19于2019年12月在中国湖北省武汉市首次被发现，导致2019年- 2020年大流行。COVID-19是由严重急性呼吸道综合征冠状病毒2（SARS-CoV- 2）。这种疾病的常见症状包括发烧、干咳、呼吸急促、腹泻和嗅觉丧失。 并发症可能包括肺炎、病毒性败血症和急性呼吸窘迫综合征。截至目前，其他 除了瑞德西韦，目前还没有被批准用于治疗COVID-19的小分子药物， 有效的疫苗仍然不确定。我们的长期目标是开发抗病毒药物， COVID-19和人类冠状病毒感染的一般情况。我们的中心假设是，抑制SARS冠状病毒， 2多聚蛋白裂解导致COVID-19的预防和早期治疗， 严重的形式。我们将确定适合开发的CoV 3C样蛋白酶（3CLpro）的纳摩尔抑制剂 作为抗病毒药物用于治疗COVID-19和其他冠状病毒感染。该提案针对 3CLpro是SARS-CoV-2多聚蛋白切割和病毒复制的关键酶。我们的总体前提是， 靶向这种必需病毒酶的小分子抑制剂将抑制复制，因此具有 可能具有预防和治疗价值。因此，我们的主要目标是设计和开发 基于结构的小分子抑制剂靶向冠状病毒3CLpro使用我们建立和证明的药物 发现的专业知识。在强有力的初步数据的指导下，多蛋白切割抑制假说将被证明是有效的。 通过追求三个具体目标进行测试：目的1）通过开发抑制SARS-CoV-2多聚蛋白切割的药物， 3CLpro（nsp 5）的共价肽抑制剂。目的2）研究抑制SARS-CoV-2多聚蛋白裂解的方法， 3CLpro（nsp 5）的非共价非肽抑制剂。和目的3）为了确定共价和 非共价SARS-CoV-2 3CLpro抑制剂在金黄仓鼠模型中的作用。在第一个目标下，铅化合物 3150及其类似物将在病毒和酶试验中测试SARS-CoV-2 3CLpro的抑制活性。一个 将在动物模型中评价3150的水溶性形式。基于结构的药物设计 将用于优化3150与SARS-CoV-2 3CLpro晶体结构的结合。根据目标2， 基于结构的虚拟筛选和杂合配体筛选方法沿着药物化学将 用于制备和评价3CLpro的非共价非肽抑制剂。在第三个目标下， SARS-CoV-2 3CLpro共价和非共价抑制剂将在一个实验室中进行药代动力学和疗效测试。 金黄仓鼠COVID-19模型。拟议研究的最终目标是推进抗COVID-19 候选药物进入提交研究性新药（IND）申请的阶段。总的来说，这一结果 该项目将产生重大的积极影响，因为它们为临床开发奠定了基础。 COVID-19抗病毒治疗以及将强效和选择性蛋白酶抑制剂与 核苷类似物（例如，Remdesivir）和如果需要的话抗炎药（例如，地塞米松或巴瑞替尼）。

PROJECT SUMMARY/ABSTRACT COVID-19 was first identified in December 2019 in Wuhan, Hubei province, China, resulting in the ongoing 2019- 2020 pandemic. COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV- 2). Common symptoms of the disease include fever, dry cough, shortness of breath, diarrhea, and loss of smell. Complications may include pneumonia, viral sepsis, and acute respiratory distress syndrome. As of today, other than remdesivir, there is no approved small molecule drug for the treatment of COVID-19 and the discovery of an effective vaccine remains uncertain. Our long-term goal is to develop antiviral drugs for the treatment of COVID-19 and human coronavirus infections in general. Our central hypothesis is that inhibition of SARS-CoV- 2 polyprotein cleavage results in the prevention and early treatment of COVID-19 before it progresses to its more severe form. We will identify nanomolar inhibitors of the CoV 3C-like protease (3CLpro) suitable to be developed as antiviral agents for the treatment of COVID-19 and other coronavirus infections. The proposal targets the 3CLpro, a key enzyme for SARS-CoV-2 polyprotein cleavage and viral replication. Our overall premise is that small molecule inhibitors targeting this essential viral enzyme will inhibit replication, and therefore have the potential to be of both preventive and therapeutic value. Thus, our primary objective is to design and develop structure-based small-molecule inhibitors targeting coronavirus 3CLpro using our established and proven drug discovery expertise. Guided by strong preliminary data, the inhibition of polyprotein cleavage hypothesis will be tested by pursuing three specific aims: Aim 1) To inhibit SARS-CoV-2 polyprotein cleavage by developing covalent peptidic inhibitors of 3CLpro (nsp5).; Aim 2) To inhibit SARS-CoV-2 polyprotein cleavage by developing noncovalent nonpeptidic inhibitors of 3CLpro (nsp5).; and Aim 3) To determine the efficacy of covalent and noncovalent SARS-CoV-2 3CLpro inhibitors in a golden hamster model. Under the first aim, lead compound 3150 and its analogs will be tested in viral and enzyme assays for inhibitory activity of SARS-CoV-2 3CLpro. An aqueous soluble form of 3150 will be evaluated in the animal model. Structure-based drug design approaches will be employed to optimize 3150 for binding to the crystal structure of SARS-CoV-2 3CLpro. Under aim 2, Structure-based virtual screening and hybrid ligand screening approaches along with medicinal chemistry will be used to prepare and evaluate noncovalent nonpeptidic inhibitors of 3CLpro. Under the third aim, top-ranked SARS-CoV-2 3CLpro covalent and noncovalent inhibitors will be tested for pharmacokinetics and efficacy in a golden hamster COVID-19 model. The ultimate goal of the proposed studies is to advance an anti-COVID-19 drug candidate to the stage of filing an investigational new drug (IND) application. Overall, the results of this project will have a significant positive impact because they lay the groundwork for the clinical development of COVID-19 antiviral therapy and the potential to combine a potent and selective protease inhibitor with a nucleoside analog (e.g., remdesivir) and if needed anti-inflammatory drugs (e.g., dexamethasone or baricitinib).