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).