Kreutzer Adam G, Krumberger Maj, Diessner Elizabeth M, Parrocha Chelsea Marie T, Morris Michael A, Guaglianone Gretchen, Butts Carter T, Nowick James S
Department of Chemistry, University of California, Irvine, CA, 92697-2025, United States.
Department of Chemistry, University of California, Irvine, CA, 92697-2025, United States; California Institute for Telecommunications and Information Technology, University of California, Irvine, CA, 92697-2025, United States.
Eur J Med Chem. 2021 Oct 5;221:113530. doi: 10.1016/j.ejmech.2021.113530. Epub 2021 May 5.
This paper presents the design and study of a first-in-class cyclic peptide inhibitor against the SARS-CoV-2 main protease (M). The cyclic peptide inhibitor is designed to mimic the conformation of a substrate at a C-terminal autolytic cleavage site of M. The cyclic peptide contains a [4-(2-aminoethyl)phenyl]-acetic acid (AEPA) linker that is designed to enforce a conformation that mimics a peptide substrate of M. In vitro evaluation of the cyclic peptide inhibitor reveals that the inhibitor exhibits modest activity against M and does not appear to be cleaved by the enzyme. Conformational searching predicts that the cyclic peptide inhibitor is fairly rigid, adopting a favorable conformation for binding to the active site of M. Computational docking to the SARS-CoV-2 M suggests that the cyclic peptide inhibitor can bind the active site of M in the predicted manner. Molecular dynamics simulations provide further insights into how the cyclic peptide inhibitor may bind the active site of M. Although the activity of the cyclic peptide inhibitor is modest, its design and study lays the groundwork for the development of additional cyclic peptide inhibitors against M with improved activities.
本文介绍了一种针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）主要蛋白酶（M）的一流环肽抑制剂的设计与研究。该环肽抑制剂旨在模拟M的C端自溶切割位点处底物的构象。环肽含有一个[4-(2-氨基乙基)苯基]乙酸（AEPA）连接子，其设计目的是强制形成一种模拟M肽底物的构象。对该环肽抑制剂的体外评估表明，该抑制剂对M表现出适度的活性，且似乎不会被该酶切割。构象搜索预测该环肽抑制剂相当刚性，采用了一种有利于与M活性位点结合的构象。对SARS-CoV-2 M进行的计算对接表明，该环肽抑制剂能够以预测的方式结合M的活性位点。分子动力学模拟进一步深入了解了环肽抑制剂可能如何结合M的活性位点。尽管环肽抑制剂的活性适中，但其设计和研究为开发具有更高活性的针对M的其他环肽抑制剂奠定了基础。
