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Saying No to SARS-CoV-2: the potential of nitric oxide in the treatment of COVID-19 pneumonia

Zhang et al., Medical Gas Research, doi:10.4103/2045-9912.385414
Nov 2023  
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Review of nitric oxide (NO) in the treatment of COVID-19. Authors summarizes evidence from in vitro studies suggesting NO has direct antiviral effects against SARS-CoV-2 as well as immune modulating and pulmonary protective effects. Small preliminary clinical trials of inhaled NO have shown mixed results for improving oxygenation in COVID-19 pneumonia patients. Of note, NO nasal spray developed by SaNOtize has received regulatory approval in several countries based on evidence it can reduce viral load in mild COVID-19 infection. Authors note that more research is needed to increase the clinical evidence and determine optimal dosing, administration method, and safety.
Zhang et al., 1 Nov 2023, peer-reviewed, 4 authors.
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Saying No to SARS-CoV-2: the potential of nitric oxide in the treatment of COVID-19 pneumonia
Honghua Zhang, Chen Zhang, Wenyan Hua, Jing Chen
Medical Gas Research, doi:10.4103/2045-9912.385414
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading around the world since 2019. Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was declared as a pandemic by the World Health Organization in March 2020. As of September 2022, it has infected more than 607 million people worldwide and claimed the lives of more than 6.5 million people. The pandemic shows no signs of slowing down and the recent emergence of more transmissible variants (Delta and Omicron) fuels a surge of infections around the world, posing a significant threat to public health as well as a tremendous social and economic burden worldwide. SARS-CoV-2 is an RNA virus closely related to SARS-CoV with 79% genetic similarity, 1 belonging to the beta-coronavirus genus. The possible modes of transmission for SARS-CoV-2 include contact, respiratory droplets, fomite, faecal-oral, mother-to-child, and animal-to-human transmission. The virus invades cells through the binding between the S protein on its surface and the host-cell receptor angiotensin-converting enzyme 2 (ACE2), which is widely distributed in various tissues and immune cells in human bodies. 2 The clinical manifestations of SARS-CoV-2 infection include fever, cough, fatigue, pneumonia, local inflammation, severe or critical disseminated intravascular coagulation, acute respiratory distress syndrome (ARDS), hypotension and multiple organ failures, some of which may eventually lead to death. 3 Nitric oxide (NO) is a signaling molecule produced from L-arginine catalyzed by NO synthase in mammalian cells. It was first discovered as an endothelium-derived relaxing factor that can activate guanylate cyclase to produce the second messenger cyclic guanosine monophosphate, finally leading to vasodilation. [4] [5] [6] The biological role of NO also involves S-nitrosation of proteins whereby NO or its derivative interacts with the thiol group of cysteine residue to form S-nitrosothiol. This post-translational modification affects countless cellular processes in physiology and pathophysiology, including the regulation of virus replication. 7, 8 Moreover, NO can cause nitration of proteins, lipids, and DNA through peroxynitrite, which is generated by the reaction of NO with superoxide anion radical, affecting various cellular processes. 9 Many studies have reported that NO plays a direct or indirect role in fighting against harmful viruses, including respiratory viruses, such as SARS-CoV-2, 10 severe acute respiratory syndrome coronavirus, 11 and influenza virus, 12 as well as non-respiratory viruses such as human papillomavirus, 13 herpes simplex virus-1 14 and porcine circovirus type 2. 15 The potential role of NO in the treatment of SARS-CoV-2 has been revealed by increasing basic and clinical studies. What's even more encouraging is the urgent approval of NO nasal spray (NONS) for the treatment of COVID-19 pneumonia in Israel, Bahrain, Thailand and Indonesia. NONS is administered
Author contributions JC designed the manuscript. HZ, CZ and WH collected literature and wrote the manuscript. JC polished the language for the manuscript. All authors read and approved the final manuscript. Conflicts of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Data availability statement No additional data are available. Open access statement This is an open access journal, and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. Note: NO mediates S-nitrosation of key proteins which are involved in virus infection, replication and other processes, resulting in changes in protein activity. For example, S-nitrosation of the new coronavirus S protein has been shown to produce an antiviral effect. Additionally, the peroxynitrite generated by the reaction of NO with superoxide anions can also cause nitration modification to the key proteins of the virus. Unlike S-nitrosation modification, nitration is irreversible and it can permanently impact the proteins' function. The NONS can be viewed as a solution of acidified nitrite that spontaneously generates NO after entering the nasal cavity. NONS directly..
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