In 2018, a Johns Hopkins team led by Amesh Adalja issued a report titled “The Characteristics of Pandemic Pathogens”, which was based on an exhaustive literature review, interviews with over 120 experts, as well as a meeting devoted to the dangers posed by pathogenic fungi, bacteria, protozoa, prions and viruses. The report concluded that viruses are the real menace. Among viruses, the most dangerous are those with an RNA-based genome because they mutate faster than DNA-based viruses and consequently develop quick resistance to antivirals.

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Importantly, when bacteria invade a mammal there is a long list of antibiotics that might help, and a single antibiotic may be used to treat many different bacterial infections. However, it is alarming to note that, while the approved treatments cover only about 5% of viral diseases, the approved antiviral drugs have only narrow targets and are effective only against a single viral subtype.

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Therefore, an urgent need exists to develop broad-spectrum antiviral drugs with a high barrier to resistance and a high therapeutic index. No matter which specific virus invades them, mammalian cells possess the same basic machinery: the usual challenge is to find a dosage high enough to damage the virus but not so elevated that it harms the host.

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The aforementioned need is more deeply felt among those concerned with developing drugs against RNA-based viruses, which are responsible for the most serious viral infections, including COVID-19, SARS and MERS, as well as among researchers and MDs fighting viruses that are able to hide in the nervous or reproductive system (Li 2020) of the host, remain in latency and provoke occasional flares.

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Together with others, we have previously provided ample evidence (reviewed recently by G. Gojón and G.A. Morales in “Antioxidants & Redox Signaling”, 2020, and published online ahead of print) that H2S protects the host cells from oxidative stress and that this protection is mediated by sulfane sulfur (SS) via increased nuclear translocation of transcription factor Nrf2 and inhibition of NADPH oxidases (Muzaffar 2008, Zimmermann 2017). This is important as viruses usually induce oxidative stress in invaded cells (Komaravelli 2014, Mathys 2016, Sebastiano 2016, Seheult 2020).                          

                  

In particular, we have established, as have others, that H2S is a lipophilic compound that is easily absorbed and distributed to all mammalian vital organs, including brain and testes; therefore, it is potentially effective against viruses hiding in a mammal’s nervous or reproductive system.

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Importantly, provision of exogenous H2S optimizes the function of a mammal’s immune system: this is actually an outstanding advantage (especially in the present context) since the subject’s immune system will then be able to better fight the viral infection as well as the concomitant dysfunctional inflammation.

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Optimization of immune function by H2S is — at least in part — explained by the H2S-cysteine-glutathone connection (please refer to the Gojón-Morales review); moreover, the broad antiviral effect of glutathione is now well established (Cai 2003, Ciriolo 1997, Diotallevi 2017, Echevarria-Lima 2018, Fraternale 2006, 2009; Kim 2020, Palamara 1995, Vasireddi 2019).

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If the viral infection affects the lungs, it is known that both endogenous and exogenous H2S exert positive effects upon the respiratory tract by modulating mucolytic activity (Viegas 2019). Furthermore, H2S inhibits virus-induced nuclear translocation of transcription factor NF-kB and effectively counteracts lung (DeDiego 2014) and myocardial inflammation (Bai 2018, Jia 2020, Pan 2013, Qian 2014, Ren 2001, Su 2008, Wu 2019, Yang 2016, Zhang 2015, Zhao 2018), as well as thrombus formation (Emerson 2015, Gang 2016, Gao 2015, Grambow 2014, 2017; Kram 2013, Wang 2014, Zagli 2007, Zaichko 2009, Zhong 2014).

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In fact, prophylactic antiviral treatment with an H2S prodrug should be instituted — or at least recommended — for all individuals at risk of viral infection and all patients presenting with metabolic syndrome, diabetes, cardiovascular or kidney dysfunction and liver problems.

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Of paramount significance is the evidence supporting the view that — at least in the cardiometabolic and cerebrovascular settings — H2S-based treatments are often capable of not only slowing disease progression, but also of reversing damage to tissues and organs (Gojón-Morales 2020 review).

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ANTIVIRAL EFFECTS OF H2S, SS AND THEIR PRODRUGS

 

It has been established that sulforaphane (an organic isothiocyanate found in broccoli) by oral administration:

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• Significantly attenuates acute inflammatory lung injury (Patel 2020);

• Protects ARDS rabbits from lung injury (Sun 2018);

• Improves the bronchoprotective response in asthmatics (Brown 2015) and;

• Significantly reduces some virus-induced markers of inflammation, as well as viral load in smokers challenged with live attenuated influenza virus (Noah 2014).

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Of note, Martelli et al. (2020) have recently concluded — in an excellent and comprehensive review — that “available literature gives convincing demonstration that H2S is the real player in isothiocyanate pharmacology”.

 

Sulforaphane’s effects have been shown to be mediated by nuclear transcription factors Nrf2 (Noah 2014, Brown 2015, Sun 2018) and Nf-kappa-beta (Heiss 2001).

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In his Ph.D. dissertation (Washington State University, 2017), A. Pacheco reported that cysteine-derived sulfur-acylated persulfides (perthiols) potently inhibit replication of several highly pathogenic enveloped viruses but have no effect on infection by a non-enveloped rotavirus. He showed that these hydrodisulfide (RSSH) precursors target the viral membrane, and therefore are not highly likely to induce viral resistance. Please note that the viral membrane is derived from the invaded cell’s cytoplasmic membrane.

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Pacheco also found that the antiviral effect of these sulfane sulfur-containing molecules is not mediated by H2S.

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A research group based at the University of Texas (Galveston, TX) — and especially interested in respiratory diseases — has published several papers (Ivanciuc 2016; Bazhanov 2017a, b; Bazhanov 2018) on the antiviral and anti-inflammatory activities of several hydrogen sulfide prodrugs (GYY4137, thiol-activated gem-dithiol-based donors).They found that, in vitro and in vivo, H2S displays broad-range antiviral activity against highly pathogenic enveloped RNA viruses.

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Overall, on the basis of available evidence, H2S prodrugs such as SG1002 are highly suitable candidates for clinical translation into safe and effective pan-antiviral agents. Since H2S is oxidatively metabolized into SS-containing molecules with great ease, we hypothesize that H2S prodrugs will exert significant antiviral effects mediated by either H2S and SS, or both.

 

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