Discovery of Novel Broad-Spectrum Coronavirus Mpro Inhibitors

项目1--摘要 本项目的目标是发现新型的广谱冠状病毒主要蛋白水解酶(MPRO)抑制剂。我们 已经获得了有希望的第一代MPRO抑制剂，具有预期的效力和类药物特性。 第一代MPRO抑制剂正在迅速进入临床开发阶段。在本申请中， 我们将利用第一代抑制剂的成功来开发第二代抑制剂。在……里面 预计未来将出现冠状病毒，第二代抑制剂将具有(I)抗病毒活性 对第一代抑制剂具有抵抗力的病毒，以及(Ii)对不同冠状病毒的覆盖范围更广。至 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型广谱- 光谱MPRO抑制剂，以预测潜在的耐药性和未来的流行病；以及(Iii)推进我们的第二个- 通过临床前开发产生广谱冠状病毒MPRO抑制剂以提供Ind-Ready 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.