Johansen-Leete Jason, Ullrich Sven, Fry Sarah E, Frkic Rebecca, Bedding Max J, Aggarwal Anupriya, Ashhurst Anneliese S, Ekanayake Kasuni B, Mahawaththa Mithun C, Sasi Vishnu M, Luedtke Stephanie, Ford Daniel J, O'Donoghue Anthony J, Passioura Toby, Larance Mark, Otting Gottfried, Turville Stuart, Jackson Colin J, Nitsche Christoph, Payne Richard J
School of Chemistry, The University of Sydney Sydney NSW 2006 Australia
Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney Sydney NSW 2006 Australia.
Chem Sci. 2022 Feb 28;13(13):3826-3836. doi: 10.1039/d1sc06750h. eCollection 2022 Mar 30.
Antivirals that specifically target SARS-CoV-2 are needed to control the COVID-19 pandemic. The main protease (M) is essential for SARS-CoV-2 replication and is an attractive target for antiviral development. Here we report the use of the Random nonstandard Peptide Integrated Discovery (RaPID) mRNA display on a chemically cross-linked SARS-CoV-2 M dimer, which yielded several high-affinity thioether-linked cyclic peptide inhibitors of the protease. Structural analysis of M complexed with a selenoether analogue of the highest-affinity peptide revealed key binding interactions, including glutamine and leucine residues in sites S1 and S2, respectively, and a binding epitope straddling both protein chains in the physiological dimer. Several of these M peptide inhibitors possessed antiviral activity against SARS-CoV-2 with EC values in the low micromolar range. These cyclic peptides serve as a foundation for the development of much needed antivirals that specifically target SARS-CoV-2.
需要能够特异性靶向严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的抗病毒药物来控制新型冠状病毒肺炎（COVID-19）大流行。主要蛋白酶（M）对SARS-CoV-2复制至关重要，是抗病毒药物开发的一个有吸引力的靶点。在此，我们报告了在化学交联的SARS-CoV-2 M二聚体上使用随机非标准肽整合发现（RaPID）mRNA展示技术，该技术产生了几种该蛋白酶的高亲和力硫醚连接环肽抑制剂。与最高亲和力肽的硒醚类似物复合的M的结构分析揭示了关键的结合相互作用，包括分别位于S1和S2位点的谷氨酰胺和亮氨酸残基，以及在生理二聚体中跨越两条蛋白质链的结合表位。这些M肽抑制剂中的几种对SARS-CoV-2具有抗病毒活性，其半数有效浓度（EC）值在低微摩尔范围内。这些环肽为开发急需的特异性靶向SARS-CoV-2的抗病毒药物奠定了基础。
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