Discovery of Novel Broad-Spectrum Coronavirus Mpro Inhibitors

新型广谱冠状病毒 Mpro 抑制剂的发现

• 批准号: 10514152
• 负责人: Julien Papillon
• 金额: $ 277.1万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514152
• 关键词: 2019-nCoV; Antiviral Agents; Binding Proteins; Biochemical; Biological Assay; COVID-19 outbreak; COVID-19 pandemic; Canis familiaris; Cardiovascular system; Caspase; Cell Line; Clinic; Clinical Research; Clinical Trials; Coronavirus; Cytochrome P450; Development; Disease Outbreaks; Dose; Drug Interactions; Ensure; Epithelial Cells; Evolution; Foundations; Funding; Future; Generations; Goals; Guidelines; Hamsters; Human; In Vitro; Individual; Infection; International; Lead; Metabolism; Middle East Respiratory Syndrome; Modeling; Monitor; Monkeys; Mus; Mutation; Neuraxis; Oral; Pathogenesis; Pathogenicity; Peptide Hydrolases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phototoxicity; Plasma Proteins; Property; Proteins; Rattus; Recovery; Resistance; Safety; Selection Criteria; Testing; Toxicology; Vaccines; Variant; Virus; Virus Replication; airway epithelium; attenuation; clinical candidate; clinical development; experimental study; fitness test; genotoxicity; good laboratory practice; human coronavirus; in vitro Assay; in vivo; inhibitor; interest; lead optimization; lead series; minimal risk; mutant; novel; novel coronavirus; pandemic coronavirus; pandemic disease; pandemic preparedness; preclinical development; programs; resistance mutation; respiratory; success; tool; zoonotic coronavirus

PROJECT 1 - ABSTRACT The goal of this project is to discover novel broad-spectrum coronavirus main protease (Mpro) inhibitors. We have already obtained promising first-generation Mpro inhibitors with desired potency and drug-like properties. The first-generation Mpro inhibitors are rapidly progressing to clinical development. In the current application, we will capitalize the success of the first-generation inhibitor to develop the second-generation inhibitor. In anticipation of future coronavirus emergence, the second-generation inhibitor will have (i) activities against viruses resistant to the first-generation inhibitor and (ii) a broader coverage against different coronaviruses. To achieve this goal, we will pursue three aims: (i) identify the antiviral spectrum of the first-generation Mpro inhibitor and evaluate the potential to induce resistance; (ii) discover and optimize a second-generation novel broad- spectrum Mpro inhibitor to anticipate potential resistance and future pandemics; and (iii) advance our second- generation broad-spectrum coronavirus Mpro inhibitor through preclinical development to deliver an IND-ready clinical candidate.

项目1 -摘要 该项目的目标是发现新型广谱冠状病毒主要蛋白酶（Mpro）抑制剂。我们 已经获得了具有所需效力和药物样性质的有希望的第一代Mpro抑制剂。 第一代Mpro抑制剂正迅速进入临床开发阶段。在当前应用中， 我们将利用第一代抑制剂的成功开发第二代抑制剂。在 预计未来冠状病毒的出现，第二代抑制剂将具有（i）抗 对第一代抑制剂具有耐药性的病毒，以及（ii）针对不同冠状病毒的更广泛覆盖。到 为了实现这一目标，我们将追求三个目标：（i）确定第一代Mpro抑制剂的抗病毒谱 并评估诱导抗性的潜力;（ii）发现并优化第二代新的广谱- 谱Mpro抑制剂，以预测潜在的耐药性和未来的流行病;和（iii）推进我们的第二- 通过临床前开发产生广谱冠状病毒Mpro抑制剂，以提供IND就绪 临床候选人