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

新型 SARS-CoV-2 蛋白酶小分子抑制剂

• 批准号: 10200270
• 负责人: Yongcheng Song
• 金额: $ 44万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200270
• 关键词: 2019-nCoV; Aldehydes; Amides; Anti-Infective Agents; Antineoplastic Agents; Antiviral Agents; Binding; Biochemical; Biological; Biological Availability; COVID-19; COVID-19 treatment; Caspase; Cells; Cessation of life; Chemicals; China; Chronic lung disease; Cleaved cell; Clinical Trials; Coronavirus Infections; Coughing; Country; Cysteine; DNA-Directed RNA Polymerase; Dangerousness; Diabetes Mellitus; Disease Outbreaks; Drug Targeting; Enzyme Inhibition; Esters; FDA Emergency Use Authorization; Fatality rate; Fatigue; Fever; Grant; Immunocompromised Host; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Lead; Libraries; Life; Lung; Lung diseases; Medical; Metabolic; Modern 1601-history; Multiple Organ Failure; Nonstructural Protein; Obesity; Organ failure; Papain; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Pneumonia; Polymerase; Polyproteins; Proteins; Prunella vulgaris; RNA Viruses; Reporting; Roentgen Rays; SARS coronavirus; SARS-CoV-2 inhibitor; Sepsis; Series; Severe Acute Respiratory Syndrome; Site; Structure-Activity Relationship; Supportive care; Symptoms; Testing; Time; Vaccines; Viral; Viral Proteins; Virus Replication; X-Ray Crystallography; base; chymotrypsin A; cytotoxicity; design; drug development; high risk; human old age (65+); improved; in vivo; inhibitor/antagonist; novel; novel coronavirus; novel therapeutics; pandemic disease; pathogen; peptidomimetics; remdesivir; reproductive; screening; small molecule inhibitor; success; swine flu; therapeutically effective; viral RNA

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.

该项目的总体目标是使用药物化学，X射线晶体学， 生物化学和生物活性测试，以开发主要蛋白酶（Mpro）的强效药物样抑制剂， SARS-CoV-2（SARS-2）是一种新型冠状病毒，可导致严重肺部疾病COVID-1的爆发。 19（冠状病毒病2019）。SARS-2在中国武汉出现，并很快传播到210多个国家 国际吧世卫组织已于2020年3月11日宣布COVID-19为全球大流行。截至6月初，SARS-2已 全球感染约700万人（确诊病例），其中美国约200万例。这些数字是 每天都在快速增长。SARS-2具有高度传染性。而大多数SARS-2感染者（81%） 相对轻微的症状，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≥65岁的人群和具有严重基础疾病的人群， 医疗条件。SARS-2已导致全球约400，000人死亡，其中包括美国的110，000人（截至2009年年初）。 2020年6月），这使其成为现代历史上最危险的病原体之一。因此有 因此，迫切需要找到有效的治疗SARS-2感染的药物和疫苗。主要蛋白酶（Mpro） SARS-2是病毒复制所必需的，因此是药物靶点。具体目标1是使用定量抑制剂 设计，药物化学和结构-活性关系（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射线晶体学和其他 生物化学/物理研究，以表征目标1中制备的化合物，这将用于指导合理的 目的1中的设计和SAR研究，以找到具有改善效力的化合物。具体目标3是执行 选择SARS-2 Mpro的有效抑制剂进行细胞毒性和细胞抗病毒活性测试，以发现 抗SARS-2和SARS-1感染的无细胞毒性、有效的抗病毒化合物。该试点项目的成功将 导致具有改进效力的小分子抑制剂，其可以强烈抑制SARS-2复制。在 此外，X射线晶体学和其他生物化学/物理研究将揭示通道-Mpro 交互.这些化合物将作为进一步药物开发的新药理学先导 针对SARS-2和其他冠状病毒感染。