Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological ActivityClick to copy article linkArticle link copied!
- Philipp FluryPhilipp FluryInstitute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, GermanyMore by Philipp Flury
- Julian BreidenbachJulian BreidenbachPharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, GermanyMore by Julian Breidenbach
- Nadine KrügerNadine KrügerInfection Biology Unit, German Primate Center, Leibniz Institute for Primate Research Göttingen, Kellnerweg 4, Göttingen 37077, GermanyMore by Nadine Krüger
- Rabea VogetRabea VogetPharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, GermanyMore by Rabea Voget
- Laura SchäkelLaura SchäkelPharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, GermanyMore by Laura Schäkel
- Yaoyao SiYaoyao SiPharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, GermanyMore by Yaoyao Si
- Vesa KrasniqiVesa KrasniqiPharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, GermanyMore by Vesa Krasniqi
- Sara CalistriSara CalistriInstitute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, GermanyMore by Sara Calistri
- Matthias OlfertMatthias OlfertFaculty of Biology and Psychology, University Göttingen, Göttingen 37073, GermanyMore by Matthias Olfert
- Katharina SylvesterKatharina SylvesterPharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, GermanyMore by Katharina Sylvester
- Cheila RochaCheila RochaInfection Biology Unit, German Primate Center, Leibniz Institute for Primate Research Göttingen, Kellnerweg 4, Göttingen 37077, GermanyMore by Cheila Rocha
- Raphael DitzingerRaphael DitzingerInstitute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, GermanyMore by Raphael Ditzinger
- Alexander RaschAlexander RaschInstitute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, GermanyMore by Alexander Rasch
- Stefan PöhlmannStefan PöhlmannInfection Biology Unit, German Primate Center, Leibniz Institute for Primate Research Göttingen, Kellnerweg 4, Göttingen 37077, GermanyFaculty of Biology and Psychology, University Göttingen, Göttingen 37073, GermanyMore by Stefan Pöhlmann
- Thales KronenbergerThales KronenbergerInstitute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, GermanyFaculty of Health Sciences, School of Pharmacy, University of Eastern Finland, Kuopio 70211, FinlandExcellence Cluster “Controlling Microbes to Fight Infections” (CMFI), Tübingen 72076, GermanyMore by Thales Kronenberger
- Antti PosoAntti PosoInstitute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, GermanyFaculty of Health Sciences, School of Pharmacy, University of Eastern Finland, Kuopio 70211, FinlandMore by Antti Poso
- Katharina RoxKatharina RoxDepartment of Chemical Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig 38124, GermanyPartner Site Hannover-Braunschweig, German Center for Infection Research (DZIF), Braunschweig 38124, GermanyMore by Katharina Rox
- Stefan A. LauferStefan A. LauferInstitute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, GermanyMore by Stefan A. Laufer
- Christa E. MüllerChrista E. MüllerPharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, GermanyMore by Christa E. Müller
- Michael Gütschow*Michael Gütschow*Email: [email protected]PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, GermanyMore by Michael Gütschow
- Thanigaimalai Pillaiyar*Thanigaimalai Pillaiyar*Email: [email protected]Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, GermanyMore by Thanigaimalai Pillaiyar
Abstract
Cathepsins (Cats) are proteases that mediate the successful entry of SARS-CoV-2 into host cells. We designed and synthesized a tailored series of 21 peptidomimetics and evaluated their inhibitory activity against human cathepsins L, B, and S. Structural diversity was realized by combinations of different C-terminal warhead functions and N-terminal capping groups, while a central Leu-Phe fragment was maintained. Several compounds were identified as promising cathepsin L and S inhibitors with Ki values in the low nanomolar to subnanomolar range, for example, the peptide aldehydes 9a and 9b (9a, 2.67 nM, CatL; 0.455 nM, CatS; 9b, 1.76 nM, CatL; 0.512 nM, CatS). The compounds’ inhibitory activity against the main protease of SARS-CoV-2 (Mpro) was additionally investigated. Based on the results at CatL, CatS, and Mpro, selected inhibitors were subjected to investigations of their antiviral activity in cell-based assays. In particular, the peptide nitrile 11e exhibited promising antiviral activity with an EC50 value of 38.4 nM in Calu-3 cells without showing cytotoxicity. High metabolic stability and favorable pharmacokinetic properties make 11e suitable for further preclinical development.
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This article is cited by 6 publications.
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- Jun-Young Park, Kyung-Min Park. Recent discovery of natural substances with cathepsin L-inhibitory activity for cancer metastasis suppression. European Journal of Medicinal Chemistry 2024, 277 , 116754. https://doi.org/10.1016/j.ejmech.2024.116754
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