Nitric oxide and viral infection: Recent developments in antiviral therapies and platforms

Abstract

Nitric oxide (NO) is a gasotransmitter of great significance to developing the innate immune response to many bacterial and viral infections, while also modulating vascular physiology. The generation of NO from the upregulation of endogenous nitric oxide synthases serves as an efficacious method for inhibiting viral replication in host defense and warrants investigation for the development of antiviral therapeutics. With increased incidence of global pandemics concerning several respiratory-based viral infections, it is necessary to develop broad therapeutic platforms for inhibiting viral replication and enabling more efficient host clearance, as well as to fabricate new materials for deterring viral transmission from medical devices. Recent developments in creating stabilized NO donor compounds and their incorporation into macromolecular scaffolds and polymeric substrates has created a new paradigm for developing NO-based therapeutics for long-term NO release in applications for bactericidal and blood-contacting surfaces. Despite this abundance of research, there has been little consideration of NO-releasing scaffolds and substrates for reducing passive transmission of viral infections or for treating several respiratory viral infections. The aim of this review is to highlight the recent advances in developing gaseous NO, NO prodrugs, and NO donor compounds for antiviral therapies; discuss the limitations of NO as an antiviral agent; and outline future prospects for guiding materials design of a next generation of NO-releasing antiviral platforms.

Keywords: ACE, angiotensin converting enzyme; AP1, activator protein 1; COVID-19; COVID-19, coronavirus disease 2019; ECMO, extracorporeal membrane oxygenation, FDA, United States Food and Drug Administration; GNSO, S-nitrosoglutathione; H1N1, influenza A virus subtype H1N1; HI, Host Immunology; HIV, human immunodeficiency virus; HPV, human papillomavirus; HSV, herpes simplex virus; I/R, pulmonary ischemia-reperfusion; IC50, inhibitory concentration 50; IFN, interferon; IFNγ, interferon gamma; IKK, inhibitor of nuclear factor kappa B kinase; IRF-1, interferon regulatory factor 1; Inhalation therapy; Medical Terminology: ARDS, acute respiratory distress syndrome; NF-κB, nuclear factor kappa-light-chain enhancer of activated B cells; NO, nitric oxide; NOS, nitric oxide synthase; Nitric Oxide and Related Compounds: eNOS/NOS 3, endothelial nitric oxide synthase; Nitric oxide; Other: DNA, deoxyribonucleic acid; P38-MAPK, P38 mitogen-activated protein kinases; PAMP, pathogen-associated molecular pattern; PCV2, porcine circovirus type 2; PHT, pulmonary hypertension; PKR, protein kinase R; RNA, ribonucleic acid; RNI, reactive nitrogen intermediate; RSNO, S-nitrosothiol; SARS, severe acute respiratory syndrome; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SNAP, S-nitroso-N-acetyl-penicillamine; STAT-1, signal transducer and activator of transcription 1; Severe acute respiratory distress; TAK1, transforming growth factor β-activated kinases-1; TLR, toll-like receptor; VAP, ventilator associated pneumonia; Viral infection; Viruses: CVB3, coxsackievirus; dsRNA, double stranded (viral) ribonucleic acid; gNO, gaseous nitric oxide; iNOS/NOS 2, inducible nitric oxide synthase; mtALDH, mitochondrial aldehyde dehydrogenase; nNOS/NOS 1, neuronal nitric oxide synthase.