Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., Tampa, FL 33620, USA.
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, 85721, USA.
Chemistry. 2023 Jun 22;29(35):e202300476. doi: 10.1002/chem.202300476. Epub 2023 May 5.
SARS-CoV-2 is still wreaking havoc all over the world with surging morbidity and high mortality. The main protease (M ) is essential in the replication of SARS-CoV-2, enabling itself an active target for antiviral development. Herein, we reported the design and synthesis of a new class of peptidomimetics-constrained α, γ-AA peptides, based on which a series of aldehyde and ketoamide inhibitors of the M of SARS-CoV-2 were prepared. The lead compounds showed excellent inhibitory activity in the FRET-based M enzymatic assay not only for the M of SARS-CoV-2 but also for SARS-CoV and MERS-CoV, along with HCoVs like HCoV-OC43, HCoV-229E, HCoV-NL63 and HKU1. The X-ray crystallographic results demonstrated that our compounds form a covalent bond with the catalytic Cys145. They also demonstrated effective antiviral activity against live SARS-CoV-2. Overall, the results suggest that α, γ-AA peptide could be a promising molecular scaffold in designing novel M inhibitors of SARS-CoV-2 and other coronaviruses.
SARS-CoV-2 仍在全球范围内肆虐，发病率和死亡率居高不下。主蛋白酶（M ）在 SARS-CoV-2 的复制中至关重要，使其成为抗病毒药物开发的一个活跃靶点。在此，我们报告了一类基于肽拟肽的新型Constrained α, γ-AA 肽的设计和合成，在此基础上，我们制备了一系列 SARS-CoV-2 M 的醛和酮酰胺抑制剂。基于荧光共振能量转移（FRET ）的 M 酶测定法，这些先导化合物不仅对 SARS-CoV-2 的 M ，而且对 SARS-CoV 和 MERS-CoV ，以及 HCoV 如 HCoV-OC43、HCoV-229E、HCoV-NL63 和 HKU1 ，均表现出优异的抑制活性。X 射线晶体学结果表明，我们的化合物与催化 Cys145 形成共价键。它们还对活 SARS-CoV-2 表现出有效的抗病毒活性。总体而言，这些结果表明，α, γ-AA 肽可能是设计新型 SARS-CoV-2 和其他冠状病毒主蛋白酶抑制剂的有前途的分子支架。
