The virally encoded 3C-like protease (3CL^pro) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CL^pro are peptidomimetic, with a γ-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the γ-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitable P1 replacement that is a potent enzymatic inhibitor of 3CL^pro in SARS-CoV-2 virus is described herein.

病毒编码的 3C 样蛋白酶 (3CL ^pro ) 是一种经过充分验证的抑制冠状病毒的药物靶点，包括严重急性呼吸系统综合症冠状病毒-2 (SARS-CoV-2)。大多数 3CL ^pro抑制剂都是肽模拟物，用 γ-内酰胺代替伪肽链 P1 位置上的谷氨酰胺。我们努力寻找 γ-内酰胺 P1 模拟物的可行替代品，该替代品将改善理化性质，同时保留对靶标的亲和力。本文描述了2-四氢呋喃作为合适的 P1 替代物的发现，它是 SARS-CoV-2 病毒中 3CL ^{pro的有效酶抑制剂。}