PT  - JOURNAL ARTICLE
AU  - Kladnik, Jerneja
AU  - Dolinar, Ana
AU  - Kljun, Jakob
AU  - Perea, David
AU  - Grau-Expósito, Judith
AU  - Genescà, Meritxell
AU  - Novinec, Marko
AU  - Buzon, Maria J.
AU  - Turel, Iztok
TI  - Zinc pyrithione is a potent inhibitor of PL<sup>Pro</sup> and cathepsin L enzymes with <em>ex vivo</em> inhibition of SARS-CoV-2 entry and replication
AID  - 10.1101/2022.03.03.482819
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.03.03.482819
4099  - http://biorxiv.org/content/early/2022/03/04/2022.03.03.482819.short
4100  - http://biorxiv.org/content/early/2022/03/04/2022.03.03.482819.full
AB  - As SARS-CoV-2 triggered a global health crisis, there is an urgent need to provide patients with safe, effective, accessible, and preferably oral therapeutics for COVID-19 that complement mRNA vaccines. Zinc compounds are widely known for their antiviral properties. Therefore, we have prepared a library of zinc complexes with pyrithione (1-hydroxy-2(1H)-pyridinethione) and its analogues, all of which showed promising in vitro inhibition of cathepsin L, an enzyme involved in SARS-CoV-2 entry, and PLPro, an enzyme involved in SARS-CoV-2 replication both in (sub)micromolar range. Zinc pyrithione 1a is a well-established, commercially available antimicrobial agent and was therefore selected for further evaluation of its SARS-CoV-2 entry and replication inhibition in an ex vivo system derived from primary human lung tissue. Our results suggest that zinc pyrithione complex 1a provides a multitarget approach to combat SARS-CoV-2 and should be considered for repurposing as a potential therapeutic against the insidious COVID-19 disease.Featured image In our study, we show that zinc pyrithione holds immense potential for the development of a possible out-patient treatment for SARS-CoV-2 due to its inhibition of viral entry and replication.Competing Interest StatementThe authors have declared no competing interest.