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Review 1: "Zinc pyrithione is a potent inhibitor of PLPro and cathepsin L enzymes with ex vivo inhibition of SARS-CoV-2 entry and replication"

This preprint reports on the activity of commercially available Zinc pyrithione 1a drug for SARS-CoV-2 entry and replication inhibition using an ex vivo system.

Published onMar 31, 2022
Review 1: "Zinc pyrithione is a potent inhibitor of PLPro and cathepsin L enzymes with ex vivo inhibition of SARS-CoV-2 entry and replication"
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key-enterThis Pub is a Review of
Zinc pyrithione is a potent inhibitor of PL<sup>Pro</sup> and cathepsin L enzymes with <i>ex vivo</i> inhibition of SARS-CoV-2 entry and replication

AbstractAs 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 imageIn 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.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.



During the pandemic, much attention was paid to zinc because of its antiviral properties.  Zinc has been suggested by Oyagbemi et al., to modulate several physiological functions including intracellular signaling, enzyme function, gustation, and olfaction, as well as reproductive, skeletal, neuronal, and cardiovascular systems1. Hence, achieving a significant therapeutic approach against COVID-19 could imply the use of zinc as a supplement together with available drugs and vaccines waiting for emergency authorization to win the battle against COVID-191. Together, it becomes innovative and creative to supplement zinc with currently available drugs and vaccines1. Zinc improves mucociliary clearance (removal of viral particles from the lungs) and strengthens the integrity of the respiratory epithelium2,3. Importantly, increased Zn2+ concentrations may also improve antiviral immunity by upregulating IFNα and preventing inflammation by inhibiting NF-κB signaling. In addition, hypozincemia's lack of zinc bioavailability is associated with loss of smell and taste1-3 a well-characterized COVID 19 symptom.  Also, low zinc concentration in the body is reported to result in higher severity of infection and mortality of COVID-19 patients 1-3.

The authors Kladnik J. et al Zinc pyrithione is a potent inhibitor of PLPro and cathepsin L enzymes with ex vivo inhibition of SARS-CoV-2 entry and replication engaged in the synthesis of zinc pyrithione complexes and use multitarget approach to evaluate their effects in combating SARS-CoV-2 infection and replication. The authors targeted the effects of the Zinc pyrithione complex on viral infectivity/ entry pathways as well as the replication processes within the cell.  With the generation of synthetic data and instrumental analysis to validate the synthesis and stability of the complexes; biochemical analysis of their effects on the possible enzymes involved in the entry and replication of the virus within the cell further the curiosity and encouraged cellular interactions’ studies.  The data presented from these studies supports the asserted conclusion and in calling for the consideration and repurposing of zinc pyrithione complexes as potential therapeutic agents against the insidious COVID -19 disease.

To support the conclusion, this study reported a library of zinc compounds containing the ligand pyrithione and its analogues prepared and tested on two SARS-CoV-2 targets enzymes, cathepsin L and PLPro . Based on the excellent results of in vitro enzyme target inhibition, further ex vivo assays were performed to investigate the inhibition of SARS-CoV-2 entry as well as its replication. This is a well-thought-out study driven by hypothesis and directed by appropriate methods.

The claims are generally justified and supported by the methods, data, interpretation of the results relative to the inhibition of enzymes responsible for the infectivity and intracellular replication of the virus in the cell. The results from this study present a strong possibility for the synthesized Zinc complexes to be a potential candidate for use as anti-covid 19 therapies.

The study is very interesting, well-written, and very informative with strong support for the author’s claim.  The claims by the authors are strongly supported by the data and methods used and provided. Decision-makers should consider the claims in this study actionable without reservation. The authors’ claim strongly supports previous work and furthers the understanding of the role of zinc in viral infection and its potential therapeutic value in COVID 19 infection. The manuscript furthered the several articles that suggested Zinc supplementation as one of the strategies to enhance the therapeutic potentials of available antiviral COVID 19 therapies.

  1. Oyagbemi, Ademola Adetokunbo et al. “Potential health benefits of zinc supplementation for the management of COVID-19 pandemic.” Journal of food biochemistry vol. 45,2 (2021): e13604. doi:10.1111/jfbc.13604

  2. Wessels, Inga et al. “The Potential Impact of Zinc Supplementation on COVID-19 Pathogenesis.” Frontiers in immunology vol. 11 1712. 10 Jul. 2020, doi:10.3389/fimmu.2020.01712

  3. Skalny, Anatoly V et al. “Zinc and respiratory tract infections: Perspectives for COVID‑19 (Review).” International journal of molecular medicine vol. 46,1 (2020): 17-26. doi:10.3892/ijmm.2020.4575

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