The recent global COVID-19 pandemic has highlighted treatments for coronavirus infection as an unmet medical need. The main protease (M^pro) has been an important target for the development of SARS-CoV-2 direct-acting antivirals. Nirmatrelvir as a covalent M^pro inhibitor was the first such approved therapy. Although M^pro inhibitors of various chemical classes have been reported, they are generally less active against nirmatrelvir-resistant variants and have limited pan-coronavirus potential, presenting a significant human health risk upon future outbreaks. We here present a novel approach and utilized DNA-encoded chemical library screening to identify the noncovalent M^pro inhibitor 5, which demonstrated a distinct binding mode to nirmatrelvir. A macrocyclization strategy designed to lock the active conformation resulted in lactone 12 with significantly improved antiviral activity. Further optimization led to the potent lactam 26, which demonstrated exceptional potency against nirmatrelvir-resistant variants as well as against a panel of viral main proteases from other coronaviruses.

中文翻译：

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来自 DNA 编码的化学库筛选命中 SARS-CoV-2 Mpro 的大环非共价抑制剂的合理设计，证明对泛冠状病毒同系物和奈马曲韦耐药变体具有有效抑制作用


最近的全球 COVID-19 大流行凸显了冠状病毒感染的治疗是一项未满足的医疗需求。主要蛋白酶 （M^pro） 一直是 SARS-CoV-2 直接作用抗病毒药物开发的重要靶标。Nirmatrelvir 作为共价 M^pro 抑制剂是第一个此类批准的疗法。尽管已经报道了各种化学类别的 M^pro 抑制剂，但它们通常对奈马曲韦耐药变体的活性较低，并且泛冠状病毒的潜力有限，在未来爆发时会对人类健康构成重大风险。我们在这里提出了一种新方法，并利用 DNA 编码的化学库筛选来鉴定非共价 M^pro 抑制剂 5，它显示出与 nirmatrelvir 的不同结合模式。旨在锁定活性构象的大环化策略导致内酯 12 具有显着提高的抗病毒活性。进一步的优化导致了有效的内酰胺 26，它对尼马曲韦耐药变体以及来自其他冠状病毒的一组病毒主要蛋白酶表现出非凡的效力。