Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Mar 1;15(5):602-609.
doi: 10.1021/acsmedchemlett.3c00562. eCollection 2024 May 9.

Identification of Dual Inhibitors Targeting Main Protease (Mpro) and Cathepsin L as Potential Anti-SARS-CoV-2 Agents

Santo Previti  1 , Roberta Ettari  1 , Elsa Calcaterra  1 , Michele Roggia  2 , Benito Natale  2 , Annabelle C Weldert  3 , Christin Müller-Ruttloff  4 , Florian Salisch  4 , Anna Irto  1 , Rosalia Maria Cigala  1 , John Ziebuhr  4 , Tanja Schirmeister  3 , Sandro Cosconati  2 , Maria Zappalà  1
Affiliations

Identification of Dual Inhibitors Targeting Main Protease (Mpro) and Cathepsin L as Potential Anti-SARS-CoV-2 Agents

Santo Previti et al. ACS Med Chem Lett. .

Abstract

In this structure-activity relationship (SAR) study, we report the development of dual inhibitors with antiviral properties targeting the SARS-CoV-2 main protease (Mpro) and human cathepsin L (hCatL). The novel molecules differ in the aliphatic amino acids at the P2 site and the fluorine position on the phenyl ring at the P3 site. The identified dual inhibitors showed Ki values within 1.61 and 10.72 μM against SARS-CoV-2 Mpro; meanwhile, Ki values ranging from 0.004 to 0.701 μM toward hCatL were observed. A great interdependency between the nature of the side chain at the P2 site and the position of the fluorine atom was found. Three dual-targeting inhibitors exhibited antiviral activity in the low micromolar range with CC50 values >100 μM. Docking simulations were executed to gain a deeper understanding of the SAR profile. The findings herein collected should be taken into consideration for the future development of dual SARS-CoV-2 Mpro/hCatL inhibitors.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Similar articles

See all similar articles

References

    1. Zhang Z.; Shen Q.; Chang H. Vaccines for COVID-19: a systematic review of immunogenicity, current development, and future prospects. Front. Immunol. 2022, 13, 84392810.3389/fimmu.2022.843928. - DOI - PMC - PubMed
    1. Shoham S.; Batista C.; Ben Amor Y.; Ergonul O.; Hassanain M.; Hotez P.; Kang G.; Kim J. H.; Lall B.; Larson H. J.; Naniche D.; Sheahan T.; Strub-Wourgaft N.; Sow S. O.; Wilder-Smith A.; Yadav P.; Bottazzi M. E. Vaccines and therapeutics for immunocompromised patients with COVID-19. EClinicalMedicine 2023, 59, 10196510.1016/j.eclinm.2023.101965. - DOI - PMC - PubMed
    1. Luxi N.; Giovanazzi A.; Arcolaci A.; Bonadonna P.; Crivellaro M. A.; Cutroneo P. M.; Ferrajolo C.; Furci F.; Guidolin L.; Moretti U.; Olivieri E.; Petrelli G.; Zanoni G.; Senna G.; Trifiro G. Allergic reactions to COVID-19 vaccines: risk factors, frequency, mechanisms and management. BioDrugs 2022, 36, 443–458. 10.1007/s40259-022-00536-8. - DOI - PMC - PubMed
    1. Yang Z. R.; Jiang Y. W.; Li F. X.; Liu D.; Lin T. F.; Zhao Z. Y.; Wei C.; Jin Q. Y.; Li X. M.; Jia Y. X.; Zhu F. C.; Yang Z. Y.; Sha F.; Feng Z. J.; Tang J. L. Efficacy of SARS-CoV-2 vaccines and the dose-response relationship with three major antibodies: a systematic review and meta-analysis of randomised controlled trials. Lancet Microbe 2023, 4, e236–e246. 10.1016/S2666-5247(22)00390-1. - DOI - PMC - PubMed
    1. Sahoo B. M.; Ravi Kumar B. V. V.; Sruti J.; Mahapatra M. K.; Banik B. K.; Borah P. Drug repurposing strategy (DRS): emerging approach to identify potential therapeutics for treatment of novel coronavirus infection. Front. Mol. Biosci. 2021, 8, 62814410.3389/fmolb.2021.628144. - DOI - PMC - PubMed

LinkOut - more resources

-