Design, synthesis and crystallographic analysis of nitrile-based broad-spectrum peptidomimetic inhibitors for coronavirus 3C-like proteases
Publication in refereed journal


摘要Coronaviral infection is associated with up to 5% of respiratory tract diseases. The 3C-like protease (3CL(pro)) of coronaviruses is required for proteolytic processing of polyproteins and viral replication, and is a promising target for the development of drugs against coronaviral infection. We designed and synthesized four nitrile-based peptidomimetic inhibitors with different N-terminal protective groups and different peptide length, and examined their inhibitory effect on the in-vitro enzymatic activity of 3CL(pro) of severe-acute-respiratory-syndrome-coronavirus. The IC50 values of the inhibitors were in the range of 4.6-49 mu M, demonstrating that the nitrile warhead can effectively inactivate the 3CL(pro) auto-cleavage process. The best inhibitor, Cbz-AVLQ-CN with an N-terminal carbobenzyloxy group, was similar to 10x more potent than the other inhibitors tested. Crystal structures of the enzyme inhibitor complexes showed that the nitrile warhead inhibits 3CL(pro) by forming a covalent bond with the catalytic Cys145 residue, while the AVLQ peptide forms a number of favourable interactions with the S1-S4 substrate-binding pockets. We have further showed that the peptidomimetic inhibitor, Cbz-AVLQ-CN, has broad-spectrum inhibition against 3CL(pro) from human coronavirus strains 229E, NL63, OC43, HKU1, and infectious bronchitis virus, with IC50 values ranging from 1.3 to 3.7 mu M, but no detectable inhibition against caspase-3. In summary, we have shown that the nitrile-based peptidomimetic inhibitors are effective against 3CL(pro), and they inhibit 3CL(pro) from a broad range of coronaviruses. Our results provide further insights into the future design of drugs that could serve as a first line defence against coronaviral infection. (C) 2012 Elsevier Masson SAS. All rights reserved.
著者Chuck CP, Chen C, Ke ZH, Wan DCC, Chow HF, Wong KB
期刊名稱European Journal of Medicinal Chemistry
頁次1 - 6
關鍵詞Coronavirus; Peptidomimetics; Protease; X-ray crystallography
Web of Science 學科類別Chemistry, Medicinal; CHEMISTRY, MEDICINAL; Pharmacology & Pharmacy

上次更新時間 2020-29-10 於 00:15