Zinc pyrithione is a potent inhibitor of PL^Pro and cathepsin L enzymes with ex vivo inhibition of SARS-CoV-2 entry and replication

Abstract

Zinc pyrithione (1a), together with its analogues 1b–h and ruthenium pyrithione complex 2a, were synthesised and evaluated for the stability in biologically relevant media and anti-SARS-CoV-2 activity. Zinc pyrithione revealed potent in vitro inhibition of cathepsin L (IC₅₀=1.88 ± 0.49 µM) and PL^Pro (IC₅₀=0.50 ± 0.07 µM), enzymes involved in SARS-CoV-2 entry and replication, respectively, as well as antiviral entry and replication properties in an ex vivo system derived from primary human lung tissue. Zinc complexes 1b–h expressed comparable in vitro inhibition. On the contrary, ruthenium complex 2a and the ligand pyrithione a itself expressed poor inhibition in mentioned assays, indicating the importance of the selection of metal core and structure of metal complex for antiviral activity. Safe, effective, and preferably oral at-home therapeutics for COVID-19 are needed and as such zinc pyrithione, which is also commercially available, could be considered as a potential therapeutic agent against SARS-CoV-2.

Graphical Abstract

Keywords:

• Antiviral agents
• SARS-CoV-2
• inhibition
• pyrithione
• zinc

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Correction

Correction Statement

This article was originally published with errors, which have now been corrected in the online version. Please see Correction (http://dx.doi.org/10.1080/14756366.2022.2126157)

Acknowledgements

The authors acknowledge EATRIS Academic Collaboration and their COVID-19 Fast Response Service for the coordination of new collaboration establishment between research group of Prof. Dr. I. Turel and Dr. María J. Buzón. We would also like to thank Maša Masič for the help with the synthesis and Tjaša Rijavec for the crystallisation of complex 1d. Schematic representation of the zinc pyrithione antiviral activity (Table of Content Graphic) was created by the artist Simon Kajtna.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The additional data that support the findings of this study are available from the corresponding author upon reasonable request. The manuscript together with SI has been uploaded to bioRxiv preprint server with https://doi.org/10.1101/2022.03.03.482819.⁸⁰

Additional information

Funding

The authors acknowledge the financial support from the Slovenian Research Agency ARRS [Research Core Funding No. P1-0175 together with an increase in research programme funding related to the COVID-19 pandemic], and the grant from the Health Department of the Government of Catalonia [DGRIS 1_5] and the Fundació La Marató TV3 [Grants 202104FMTV3 and 202112FMTV3] to M.G. and MJ.B. MJ.B is supported by the Miguel Servet Program funded by the Spanish Health Institute Carlos III [CP17/00179].