Thiol-Activated Hydrogen Sulfide Donors Antiviral and Anti-Inflammatory Activity in Respiratory Syncytial Virus Infection.

Nikolay Bazhanov,Antonella Casola,Ming Xian,Jianming Kang,Matteo Garofalo,Haotian Wu,Teodora Ivanciuc

doi:10.3390/v10050249

Abstract

We have recently shown that endogenous hydrogen sulfide (H2S), an important cellular gaseous mediator, exerts an antiviral and anti-inflammatory activity in vitro and in vivo, and that exogenous H2S delivered via the synthetic H2S-releasing compound GYY4137 also has similar properties. In this study, we sought to extend our findings to a novel class of H2S donors, thiol-activated gem-dithiol-based (TAGDDs). In an in vitro model of human respiratory syncytial virus (RSV) infection, TAGDD-1 treatment significantly reduced viral replication, even when added up to six hours after infection. Using a mouse model of RSV infection, intranasal delivery of TAGDD-1 to infected mice significantly reduced viral replication and lung inflammation, markedly improving clinical disease parameters and pulmonary dysfunction, compared to vehicle treated controls. Overall our results indicate that this novel synthetic class of H2S-releasing compounds exerts antiviral and anti-inflammatory activity in the context of RSV infection and represents a potential novel pharmacological approach to ameliorate viral-induced lung disease.

Highlights

Hydrogen sulfide (H2 S) is an endogenous gaseous transmitter that acts as an intracellular messenger molecule, playing physiological roles in a variety of functions such as synaptic transmission, vascular tone, angiogenesis, inflammation, and cellular signaling
In recent studies we found that endogenous H2 S has an antiviral and anti-inflammatory role against respiratory syncytial virus (RSV) [8,9], which represent a major cause of pediatric upper and lower respiratory tract infections [10]
Our results show that Thiol-Activated gem-Dithiol-based H2 S donors (TAGDD) have significant antiviral activity against RSV in vitro and they inhibit lung inflammation and reduce viral replication in a mouse model of infection, leading to significant amelioration of clinical illness, they represent a potential novel pharmacological approach to ameliorate RSV-induced lung disease

Summary

Introduction

Hydrogen sulfide (H2 S) is an endogenous gaseous transmitter that acts as an intracellular messenger molecule, playing physiological roles in a variety of functions such as synaptic transmission, vascular tone, angiogenesis, inflammation, and cellular signaling. Changes in H2 S cellular levels have been associated with the pathophysiology of acute and chronic lung diseases such asthma, chronic obstructive pulmonary disease, pulmonary fibrosis and hypoxia-induced pulmonary hypertension, as it regulates airway bronchoconstriction, pulmonary circulation, fibrosis, oxidative stress, and inflammation (reviewed in [1]). As a number of airway diseases are associated with lower H2 S cellular levels, the use of H2 S donors may represent an important therapeutic approach to increase H2 S tissue. A number of H2 S donors exist that include inorganic salts, compounds with organic backbones, amino-acids, and naturally occurring compounds. Sulfide salts, such as sodium hydrosulfide (NaHS)

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