Preparation of SARS-CoV 3CL protease and synthesis of its inhibitors

Severe acute respiratory syndrome (SARS) is a contagious respiratory disease in humans which is caused by the SARS-CoV. The key enzyme in the processing of polyproteins pp1a and pp1ab, translated by the viral RNA genome of SARS-CoV is called a 3CL protease. Due to its functional importance in the viral life cycle, SARS-CoV 3CL protease is considered to be an attractive target for a drug for SARS therapy. In a research program on SARS 3CL protease, we found for the first time that mature SARS 3CL protease is subject to degradation at the 188Arg/189Gln site, and prepared R188I mutant protease with high activity and stability. Next, practical synthetic routes for the preparation of peptide aldehydes on a solid support were investigated. Efficient transformation of acetal/thioacetal structures as a key step was employed. For the application of the methodology, we designed and synthesized the tetrapeptide aldehyde Ac-Thr-Val-Cha-His-H with an IC 50 value of 98 nM against SARS 3CL protease. In addition, we found new scaffolds, phenylisoserine and decaisoquinoline derivatives connected with the essential functional groups to show the potent inhibitory activities against SARS 3CL protease. © 2021 Society of Synthetic Organic Chemistry. All rights reserved.