4.1 Endogenous and exogenous sources of hydrogen sulfide
In the search for antiviral agents for effective treatment of COVID-19, hydrogen sulfide (H2S), a pungent-smelling gas which gained notoriety for several centuries for its toxicity and death among industrial and agricultural workers, is emerging as a potential candidate drug. Over the last two decades, however, H2S has moved past its historic notorious label as a gas which was once feared, to a volatile intracellular messenger molecule that plays important roles in cellular homeostasis and impact physiological and pathophysiological conditions, including regulation of the renal system (Wang, 2002). H2S possesses important therapeutic properties including antiviral, anti-inflammatory, anti-thrombotic and antioxidant properties, which are important for any drug candidate against COVID-19. Endogenous H2S is produced in mammalian cells by four enzymatic pathways. The first two pathways involve the use of the substrate L-cysteine, a sulfur-containing amino acid, in the presence of two cytosolic enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) while the third pathway uses the mitochondrial enzyme 3-mecaptopyruvate sulfurtransferase (3-MST) and the intermediate product 3-mecaptopyruvate (from L-cysteine). The fourth enzymatic pathway uses D-cysteine, an enantiomer of L-cysteine, and the peroxisomal enzyme D-amino acid oxidase (DAO) (Xia et al., 2009; Mikami et al., 2011; Modis et al., 2013; Shibuya et al., 2013). Reduced production of endogenous H2S and expression of these H2S-producing enzymes have been associated with various pathologies of the organ system including the renal system. Whereas the distribution of these H2S-producing enzymes are tissue specific, we and others have previously reported that all the four enzymes are abundantly expressed in the glomerular and tubular compartments of the kidney (Shibuya et al., 2013; Yamamoto et al., 2013; Dugbartey et al., 2015a; Tomita et al., 2016). This makes the kidney is a richer source of endogenous H2S production compared to other organs.
In addition to its endogenous production, H2S is also administered exogenously in its gaseous form (though less ideal) and via H2S donor compounds. These H2S donors include water-soluble, fast-releasing but short-lasting H2S donors such as the inorganic sulfide salts, sodium hydrosulfide (NaHS) and sodium sulfide (Na2S) (Kulkarni et al., 2009). There is also water-soluble, slow- and controlled-releasing, long-lasting H2S donor donor GYY4137 (Li et al., 2008), and mitochondrially-targeted slow-releasing donors AP39 and AP123 (Gero et al., 2016), which augment mitochondrial H2S production by 3-MST and provide an effective and longer treatment time in experimental models of kidney diseases including acute kidney injury, chronic kidney disease, diabetic nephropathy, hypertensive kidney injury, renal cancer, drug-induced nephropathy, renal ischemia-reperfusion injury and kidney transplantation. As already discussed in previous sections, all these pathological conditions involving the kidney are worsened by COVID-19 infection. While these H2S donors are limited to only preclinical studies, thiosulfate, a major H2S oxidation product in the form of sodium thiosulfate (STS), is an FDA-approved drug already in clinical use for treatment of calciphylaxis in ESRD patients and other clinical situations (Strazzula et al., 2013). Other clinically viable H2S donor drugs such as ATB-346 (H2S-generating naproxen molecule) and zofenopril (FDA-approved antihypertensive drug that increases H2S release) are currently in human clinical trials for gastric ulcer, osteoarthritis, chronic pain, cardiovascular diseases and type 2 diabetes mellitus (www.clinicaltrials.gov).