%0 Journal Article
%A Gao, Shenghua
%A Sylvester, Katharina
%A Song, Letian
%A Claff, Tobias
%A Jing, Lanlan
%A Woodson, Molly
%A Weiße, Renato H.
%A Cheng, Yusen
%A Schäkel, Laura
%A Petry, Marvin
%A Gütschow, Michael
%A Schiedel, Anke C.
%A Sträter, Norbert
%A Kang, Dongwei
%A Xu, Shujing
%A Toth, Karoly
%A Tavis, John
%A Tollefson, Ann E.
%A Müller, Christa E.
%A Liu, Xinyong
%A Zhan, Peng
%T Discovery and Crystallographic Studies of Trisubstituted Piperazine Derivatives as Non-Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity and Low Toxicity
%J Journal of medicinal chemistry
%V 65
%N 19
%@ 0022-2623
%C Washington, DC
%I ACS
%M PUBDB-2022-05094
%P 13343 - 13364
%D 2022
%Z Waiting for fulltext 
%X The continuous spread of SARS-CoV-2 calls for more direct-acting antiviral agents to combat the highly infectious variants. The main protease (Mpro) is an promising target for anti-SARS-CoV-2 drug design. Here, we report the discovery of potent non-covalent non-peptide Mpro inhibitors featuring a 1,2,4-trisubstituted piperazine scaffold. We systematically modified the non-covalent hit MCULE-5948770040 by structure-based rational design combined with multi-site binding and privileged structure assembly strategies. The optimized compound GC-14 inhibits Mpro with high potency (IC50 = 0.40 μM) and displays excellent antiviral activity (EC50 = 1.1 μM), being more potent than Remdesivir. Notably, GC-14 exhibits low cytotoxicity (CC50 > 100 μM) and excellent target selectivity for SARS-CoV-2 Mpro (IC50 > 50 μM for cathepsins B, F, K, L, and caspase 3). X-ray co-crystal structures prove that the inhibitors occupy multiple subpockets by critical non-covalent interactions. These studies may provide a basis for developing a more efficient and safer therapy for COVID-19.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:36107752
%U <Go to ISI:>//WOS:000858874600001
%R 10.1021/acs.jmedchem.2c01146
%U https://bib-pubdb1.desy.de/record/483025