Abstract：
The development of novel antivirals is crucial not only for managing current COVID-19 infections but for addressing potential future zoonotic outbreaks. SARS-CoV-2 main protease (Mpro) is vital for viral replication and viability and therefore serves as an attractive target for antiviral intervention. Herein, we report the optimization of a cyclic peptide inhibitor that emerged from an mRNA display selection against the SARS-CoV-2 Mpro to enhance its cell permeability and in vitro antiviral activity. By identifying mutation-tolerant amino acid residues within the peptide sequence, we describe the development of a second-generation Mpro inhibitor bearing five cyclohexylalanine residues. This cyclic peptide analogue exhibited significantly improved cell permeability and antiviral activity compared to the parent peptide. This approach highlights the importance of optimizing cyclic peptide hits for activity against intracellular targets such as the SARS-CoV-2 Mpro.
摘要：
新型抗病毒药物的开发不仅对于管理当前的COVID-19感染，而且对于解决未来潜在的人畜共患疫情至关重要。SARS-CoV-2主要蛋白酶（Mpro）对于病毒复制和生存力至关重要，因此可作为抗病毒干预的有吸引力的靶标。在这里，我们报道了针对SARS-CoV-2Mpro的mRNA展示选择产生的环肽抑制剂的优化，以增强其细胞通透性和体外抗病毒活性。通过鉴定肽序列中的突变耐受氨基酸残基,我们描述了带有五个环己基丙氨酸残基的第二代Mpro抑制剂的开发。与亲本肽相比,该环肽类似物表现出显著改善的细胞渗透性和抗病毒活性。这种方法突出了优化环状肽命中针对针对细胞内靶标(例如SARS-CoV-2Mpro)的活性的重要性。
