Anti-inflammatory and antiviral roles of hydrogen sulfide: Rationale for considering H2 S donors in COVID-19 therapy

Abstract

The COVID-19 pandemic caused by SARS-Cov-2 demands rapid, safe and effective therapeutic options. In the last decades, the endogenous gasotransmitter hydrogen sulfide (H₂ S) has emerged as modulator of several biological functions and its deficiency has been associated with different disorders. Therefore, many H₂ S-releasing agents have been developed as potential therapeutic tools for diseases related with impaired H₂ S production and/or activity. Some of these compounds are in advanced clinical trials. Presently, the pivotal role of H₂ S in modulating the inflammatory response and pro-inflammatory cytokine cascade is well recognized, and the usefulness of some H₂ S-donors for the treatment of acute lung inflammation has been reported. Recent data is elucidating several mechanisms of action, which may account for antiviral effects of H₂ S. Noteworthy, some preliminary clinical results suggest an inverse relationship between endogenous H₂ S levels and severity of COVID-19. Therefore, repurposing of H₂ S-releasing drugs may be a potential therapeutic opportunity for treatment of COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

Keywords: COVID-1; H2S-donor; SARS-CoV-2; drug repurposing; hydrogen sulfide.

FIGURE 1

Role of H₂S in lung inflammation. H₂S shows many beneficial effects in lung inflammation disease. In particular, (a) H₂S is able to break mucin disulfide bonds, making the mucus less viscous and easier to be expelled by the respiratory ciliary apparatus, facilitating the elimination of potentially harmful viruses or extraneous particles. (b) H₂S blocks activation of the NF‐κB pathway, through the sulfhydration and inhibition of IKκβ enzyme, preventing the translocation of NF‐κB into the nucleus, thus preventing generation of the cytokine storm. (c) H₂S promotes the activation of Nrf2, enhancing the expression of antioxidant molecules and enzymes. Moreover, H₂S is endowed with direct antioxidant activity, thus protecting the tissues from the oxidative stress. (d) H₂S activates K_ATP channels expressed on the cell membrane of bronchial smooth muscle cells, promoting bronchodilation, and blocks the Na⁺/K⁺ ATPase pump, triggering electrolyte absorption and enhancing mucociliary clearance

FIGURE 2

Potential mechanisms of H₂S donors as anti‐COVID‐19 agents