Macrocyclic peptides have garnered significant attention as promising drug candidates. However, they typically face challenges in achieving and enhancing cell permeability for access to intracellular targets. In this study, we focused on the de novo screening of macrocyclic peptide inhibitors against the main protease (Mpro) of SARS-CoV-2 and identified novel noncovalently bound macrocyclic peptides that effectively inhibit proteolytic activity. High-resolution crystal structures further revealed molecular interactions between the macrocyclic peptides and Mpro. Subsequently, a specific macrocyclic peptide lacking cell permeability was further optimized and transformed into a low-toxicity, metabolically stable bicyclic peptide with a cell penetration capacity and therapeutic potential against SARS-CoV-2. The bicyclic peptide was achieved using a novel strategy that involved introducing both a bicyclic structure and a bridging perfluorobiphenyl group. Our study not only provides a lead peptide inhibitor for COVID-19 but also offers valuable insights into achieving cell penetration for macrocyclic peptides through strategic modifications.

中文翻译：

---

从头发现一种靶向 SARS-CoV-2 主要蛋白酶的非共价细胞穿透性双环肽抑制剂


大环肽作为有前途的候选药物引起了广泛关注。然而，它们通常面临在实现和增强细胞通透性以进入细胞内靶标方面面临的挑战。在这项研究中，我们专注于针对 SARS-CoV-2 主要蛋白酶 （Mpro） 的大环肽抑制剂的从头筛选，并确定了有效抑制蛋白水解活性的新型非共价结合大环肽。高分辨率晶体结构进一步揭示了大环肽和 Mpro 之间的分子相互作用。随后，一种缺乏细胞通透性的特异性大环肽被进一步优化并转化为低毒性、代谢稳定的双环肽，具有针对 SARS-CoV-2 的细胞渗透能力和治疗潜力。双环肽是使用一种新策略实现的，该策略涉及引入双环结构和桥接全氟联苯基团。我们的研究不仅为 COVID-19 提供了先导肽抑制剂，还为通过战略修饰实现大环肽的细胞渗透提供了有价值的见解。