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.

该项目的总体目的是结合医学化学，X射线晶体学， 生化和生物学活性测试，以产生主要蛋白（MPRO）的有效的药物样抑制剂 SARS-COV-2（SARS-2），一种新型冠状病毒，导致严重的肺部疾病爆发 19（2019年冠状病毒病）。 SARS-2在中国武汉出现，很快传播到> 210个国家 全世界。谁在2020年3月11日宣布Covid-19是全球大流行。截至6月初，SARS-2已有 全球受感染约700万人（已确认的案件），其中包括约200万例案件。这些数字是 每天迅速增长。 SARS-2具有高度传染性。而大多数感染SARS-2的患者（81％）显示 相关的轻度症状，威胁生命的严重疾病，包括严重的肺炎，败血症和器官衰竭， 可能会出现≥65岁的人的风险明显更高，并且有严重的人 医疗状况。 SARS-2在全球造成约400,000人死亡，包括美国> 110,000人（截至早期 2020年6月），这使其成为现代历史上最危险的病原体之一。因此有一个 紧迫需要找到有效的疗法和SARS-2感染的疫苗。主蛋白（MPRO） SARS-2对于病毒复制至关重要，因此是药物靶标的。特定目的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，以发现更多的潜在抑制剂 SARS-2 MPRO。具体目标2是执行酶抑制作用，X射线晶体学和其他 生化/物理研究以表征AIM 1中的化合物，该化合物将用于指导理性 在AIM 1中的设计和SAR研究以找到具有提高效力的化合物。特定目标3是执行 SARS-2 MPRO选定有效抑制剂的细胞毒性和细胞抗病毒活性测试，以便找到 针对SARS-2和-1感染的非毒性，潜在的抗病毒化合物。这个试点项目的成功将 导致小分子抑制剂具有提高的效力，可以强烈抑制SARS-2复制。在 另外，X射线晶体学和其他生化/物理研究将揭示抑制剂-MPRO 互动。这些化合物将作为进一步的药物开发的新药理铅 靶向SARS-2和其他冠状病毒感染。