Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity
机构：[1]Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.[2]Platform Infection Models, German Primate Center, Leibniz Institute for Primate Research Göttingen, Kellnerweg 4, 37077 Göttingen, Germany.[3]PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.[4]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[5]Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Kellnerweg 4, Göttingen 37077, Germany.[6]Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil.[7]Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0657, United States.[8]Faculty of Biology and Psychology, Georg-August University Göttingen, Göttingen, 37073, Germany.[9]School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio 70211, Finland.[10]German Center for Infection Research (DZIF), Partner Site Tübingen, Elfriede-Aulhorn-Str. 6, Tübingen 72076, Germany.[11]Department of Chemical Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig 38124, Germany.[12]German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig 38124, Germany.[13]Center for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, Leipzig 04103, Germany.[14]Cluster of Excellence "Image Guided and Functionally Instructed Tumor Therapies" (iFIT), Eberhard Karls University of Tuebingen, Tuebingen 72076, Germany.
The main protease (Mpro) of SARS-CoV-2 is a key drug target for the development of antiviral therapeutics. Here, we designed and synthesized a series of small-molecule peptidomimetics with various cysteine-reactive electrophiles. Several compounds were identified as potent SARS-CoV-2 Mpro inhibitors, including compounds 8n (IC50 = 0.0752 μM), 8p (IC50 = 0.0887 μM), 8r (IC50 = 0.0199 μM), 10a (IC50 = 0.0376 μM), 10c (IC50 = 0.0177 μM), and 10f (IC50 = 0.0130 μM). Most of them additionally inhibited cathepsin L and were also active against SARS-CoV-1 and MERS-CoV Mpro. In Calu-3 cells, several inhibitors, including 8r, 10a, and 10c, displayed high antiviral activity in the nanomolar range without showing cellular toxicity. The cocrystal structure of SARS-CoV-2 Mpro in complex with 8p revealed covalent binding to the enzyme's catalytic residue Cys145 and showed specific, unprecedented interactions within the substrate binding pocket. Compounds 10c and especially 8n were effective against a panel of naturally occurring nirmatrelvir-resistant mutants, particularly E166V, and showed metabolic stability and additional favorable pharmacokinetic properties, making it a suitable candidate for further preclinical development.
基金：
We are grateful for support by the Volkswagen-
Stiftung, Germany (9A894 to C.E.M. and M.G. and 9A850 to
N.S.). We acknowledge DESY (Hamburg, Germany), a member
of the Helmholtz Association HGF, and the EMBL for the
provision of experimental facilities at synchrotron beamlines
P13 and P14 and the MX Laboratory at the Helmholtz Zentrum
Berlin (BESSY II) for beam time. We would like to thank Kirill
Kovalev for assistance in using the EMBL beamlines.
语种：
外文
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大类|1 区医学
小类|1 区药物化学
第一作者：
第一作者机构：[1]Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
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推荐引用方式(GB/T 7714)：
Philipp Flury,Nadine Krüger,Katharina Sylvester,et al.Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity[J].Journal Of Medicinal Chemistry.2025,doi:10.1021/acs.jmedchem.4c02254.
APA：
Philipp Flury,Nadine Krüger,Katharina Sylvester,Julian Breidenbach,Ghazl Al Hamwi...&Thanigaimalai Pillaiyar.(2025).Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity.Journal Of Medicinal Chemistry,,
MLA：
Philipp Flury,et al."Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity".Journal Of Medicinal Chemistry .(2025)
医学