Discovery of Novel Broad-Spectrum Coronavirus Mpro Inhibitors

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;（ii）针对不同冠状病毒的更广泛覆盖范围。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

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.