Broad-Range Antiviral Activity of Hydrogen Sulfide Against Highly Pathogenic RNA Viruses

Abstract

Hydrogen sulfide is an important endogenous mediator that has been the focus of intense investigation in the past few years, leading to the discovery of its role in vasoactive, cytoprotective and anti-inflammatory responses. Recently, we made a critical observation that H2S also has a protective role in paramyxovirus infection by modulating inflammatory responses and viral replication. In this study we tested the antiviral and anti-inflammatory activity of the H2S slow-releasing donor GYY4137 on enveloped RNA viruses from Ortho-, Filo-, Flavi- and Bunyavirus families, for which there is no FDA-approved vaccine or therapeutic available, with the exception of influenza. We found that GYY4137 significantly reduced replication of all tested viruses. In a model of influenza infection, GYY4137 treatment was associated with decreased expression of viral proteins and mRNA, suggesting inhibition of an early step of replication. The antiviral activity coincided with the decrease of viral-induced pro-inflammatory mediators and viral-induced nuclear translocation of transcription factors from Nuclear Factor (NF)-kB and Interferon Regulatory Factor families. In conclusion, increasing cellular H2S is associated with significant antiviral activity against a broad range of emerging enveloped RNA viruses, and should be further explored as potential therapeutic approach in relevant preclinical models of viral infections.

The influence of spaceflight on the astronaut salivary microbiome and the search for a microbiome biomarker for viral reactivation

“…Lactate also significantly increases the production of hydrogen sulfide (H 2 S) by Veillonella [39,40]. H 2 S has been shown to be protective against pathogenic RNA viruses by decreasing the expression of viral proteins and mRNA during the early stages of replication, [41,42] though no studies have been published regarding its protective capacity against DNA viruses. Veillonella, one of the major H 2 S producers in the oral cavity [43], had a significantly (p < 0.05) higher relative abundance in samples that came from subjects that never had a reactivation episode compared to samples that were negative for virus but came from subjects that had a reactivation episode at least once ( Figure S4A).…”

Hydrogen sulfide in physiology and pathogenesis of bacteria and viruses

“…H 2 S has also been shown to affect replication of highly pathogenic enveloped RNA virus from Ortho‐, Filo‐, Flavi‐, and Bunyavirus families (Fig. ) . FDA approved antiviral treatment is available for influenza virus ( Orthomyxoviridae ), whereas there is no vaccine or therapeutic interventions to target Ebola virus ( Filoviridae ), Far‐eastern subtype tick‐borne flavivirus ( Flaviviridae ), Rift valley fever virus and Crimean‐Congo hemorrhagic fever virus ( Bunyaviridae ) .…”

Recent Advances in the Development of Antiviral Therapeutics for Rift Valley Fever Virus Infection

“…In a respiratory syncytial virus mouse model, intranasal (IN) administrered GYY4137 resulted in reduction of viral titers following IN infection with 10 7 pfu, in the lung and airway inflammation, and in an overall improved disease outcome [142]. In a recent publication, the broad-spectrum antiviral activity of GYY4137 was demonstrated against RVFV and Crimean-Congo hemorrhagic fever virus, as well as influenza virus, Ebola virus and far-eastern subtype tick-borne encephalitis flavivirus [143]. In the case of RVFV (MOI = 1), viral titers and levels of viral RNA were significantly reduced in vitro compared with nontreated cells.…”

“…6051, 7007 NP oligomerization inhibition Ͻ0.4 μM (Vero E6) [109] Suramin vRNA/N Interaction 22.3 μM (HEK 293T) [110] BCX4430 Adenosine analog inhibiting RNA polymerase 41.6 μM (HeLa) C57/BL6 mice [113,114] Six related compounds Not known 2.1-7.0 μM (A549) [115] LJ001, JL-compound series Membrane disruption Ͻ0.5 μM (BHK-S) BALB/c mice [93,118] Sorafanib RNA synthesis, egress 6.4 μM (Vero) BALB/c mice [119] Bortezomib Ubiquitin proteasome inhibitor Ͻ0.01 μM (HSAEC) [122] FGI-106 Unknown host protein 800 nM (Vero E6) [123] Rapamycin mTOR Inhibition 11 μM (H2. 35) BALB/c mice [129] 17AAG, BAPT A-AM HSP90 Inhibition Ͻ10 μM (Vero) [130] 5,6-dimethoxyindan-1-one Undefined 0.73 μg/ml [131] 1E7-03 PP1 inhibition 3.5 μM (HSAEC03) [136] 25HC Viral-cell membrane fusion block Ͻ1 μM (HeLa) [137] GYY4137 (H2S-donor) Reactive species scavenger Ͻ5 mM (Vero) [143] Four signal transduction inhibitors Block early stages of infection 4.7-36.4 μM (HeLa) [145] Four protease inhibitors Proteasome system inhibition 13.6-61.5 μM (HeLa) [146] RNASEK Internalization block siRNA knockdown [147] SMER28 Autohagy inhibition 6.9 μM (U2OS) [124] NSC 62914 Reactive species scavenger Ͻ10 μM (A549) C57/BL6 mice [151] RNA aptamers RNA binding inhibition Not determined [112] GC stem fragment Peptide fusion inhibition Not determined [159] † In vitro cell culture system used to evaluate antiviral activity against Rift Valley fever virus. and manageable diseases [72,73].…”