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

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2158-2168. doi: 10.1080/14756366.2022.2108417.

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 PLPro (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.

Keywords: Antiviral agents; SARS-CoV-2; inhibition; pyrithione; zinc.

MeSH terms

  • Antiviral Agents / pharmacology
  • COVID-19 Drug Treatment*
  • Cathepsin L
  • Humans
  • Organometallic Compounds
  • Pyridines
  • Ruthenium*
  • SARS-CoV-2

Substances

  • Antiviral Agents
  • Organometallic Compounds
  • Pyridines
  • Ruthenium
  • Cathepsin L
  • pyrithione zinc

Grants and 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].