Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections
- PMID: 37853179
- PMCID: PMC10584882
- DOI: 10.1038/s42003-023-05317-9
Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections
Abstract
Several drug screening campaigns identified Calpeptin as a drug candidate against SARS-CoV-2. Initially reported to target the viral main protease (Mpro), its moderate activity in Mpro inhibition assays hints at a second target. Indeed, we show that Calpeptin is an extremely potent cysteine cathepsin inhibitor, a finding additionally supported by X-ray crystallography. Cell infection assays proved Calpeptin's efficacy against SARS-CoV-2. Treatment of SARS-CoV-2-infected Golden Syrian hamsters with sulfonated Calpeptin at a dose of 1 mg/kg body weight reduces the viral load in the trachea. Despite a higher risk of side effects, an intrinsic advantage in targeting host proteins is their mutational stability in contrast to highly mutable viral targets. Here we show that the inhibition of cathepsins, a protein family of the host organism, by calpeptin is a promising approach for the treatment of SARS-CoV-2 and potentially other viral infections.
© 2023. Springer Nature Limited.
Conflict of interest statement
The authors declare no competing interests.
Figures
![Fig. 1](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/10584882/bin/42003_2023_5317_Fig1_HTML.gif)
![Fig. 2](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/10584882/bin/42003_2023_5317_Fig2_HTML.gif)
![Fig. 3](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/10584882/bin/42003_2023_5317_Fig3_HTML.gif)
![Fig. 4](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/10584882/bin/42003_2023_5317_Fig4_HTML.gif)
![Fig. 5](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/10584882/bin/42003_2023_5317_Fig5_HTML.gif)
Similar articles
-
MPI8 is Potent against SARS-CoV-2 by Inhibiting Dually and Selectively the SARS-CoV-2 Main Protease and the Host Cathepsin L.ChemMedChem. 2022 Jan 5;17(1):e202100456. doi: 10.1002/cmdc.202100456. Epub 2021 Jul 29. ChemMedChem. 2022. PMID: 34242492 Free PMC article.
-
Challenges for Targeting SARS-CoV-2 Proteases as a Therapeutic Strategy for COVID-19.ACS Infect Dis. 2021 Jun 11;7(6):1457-1468. doi: 10.1021/acsinfecdis.0c00815. Epub 2021 Feb 11. ACS Infect Dis. 2021. PMID: 33570381 Free PMC article.
-
Novel dithiocarbamates selectively inhibit 3CL protease of SARS-CoV-2 and other coronaviruses.Eur J Med Chem. 2023 Mar 15;250:115186. doi: 10.1016/j.ejmech.2023.115186. Epub 2023 Feb 6. Eur J Med Chem. 2023. PMID: 36796300 Free PMC article.
-
Targeting the Dimerization of the Main Protease of Coronaviruses: A Potential Broad-Spectrum Therapeutic Strategy.ACS Comb Sci. 2020 Jun 8;22(6):297-305. doi: 10.1021/acscombsci.0c00058. Epub 2020 May 27. ACS Comb Sci. 2020. PMID: 32402186 Review.
-
Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure-Activity Relationship Insights and Evolution Perspectives.J Med Chem. 2022 Oct 13;65(19):12500-12534. doi: 10.1021/acs.jmedchem.2c01005. Epub 2022 Sep 28. J Med Chem. 2022. PMID: 36169610 Free PMC article. Review.
Cited by
-
SARS-CoV-2 Mpro responds to oxidation by forming disulfide and NOS/SONOS bonds.Nat Commun. 2024 May 7;15(1):3827. doi: 10.1038/s41467-024-48109-3. Nat Commun. 2024. PMID: 38714735 Free PMC article.
-
Structural Elucidation and Antiviral Activity of Covalent Cathepsin L Inhibitors.J Med Chem. 2024 May 9;67(9):7048-7067. doi: 10.1021/acs.jmedchem.3c02351. Epub 2024 Apr 17. J Med Chem. 2024. PMID: 38630165 Free PMC article.
-
Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity.ACS Pharmacol Transl Sci. 2024 Jan 19;7(2):493-514. doi: 10.1021/acsptsci.3c00313. eCollection 2024 Feb 9. ACS Pharmacol Transl Sci. 2024. PMID: 38357286
References
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical
Miscellaneous