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The potential role of inhaled nitric oxide for postexposure chemoprophylaxis of COVID-19

Abstract

Background

Several vaccines have been fast-tracked in an attempt to decrease the morbidity and mortality of COVID-19. However, post-exposure prophylaxis has been overlooked in battling COVID-19.

Main text

Inhaled nitric oxide is a potential tool in post-exposure prophylaxis of COVID-19. It decreases cytosolic calcium levels, which impairs the action of Furin. SARS-CoV-2 uses Furin to replicate in the respiratory tract.

Short conclusion

Inhaled nitric oxide could decrease the viral load in the upper respiratory tract, abort clinically symptomatic infection, and prevent subsequent complications. Nitric oxide might be a tool for post-exposure chemoprophylaxis in at-risk groups, especially medical personnel.

Background

SaNOtize (Canada, Vancouver-based/NCT04443868 biotech firm) recently created a self-administered nitric oxide nasal spray (NONS) that could potentially reduce coronavirus disease 2019 (COVID-19) viral load in infected patients. After completing early-stage clinical trials in Canada and the United Kingdom (UK), SaNOtize, Ashford and St. Peter’s Hospitals, the National Hospital System (NHS) foundation, and a few pathology services in the UK announced the results of phase II trials. The results indicate that NONS can be a powerful and safe antiviral treatment. It could prevent COVID-19 transmission, shorten its duration, and reduce the severity of its symptoms.

Some reports have discussed the use of nitric oxide against COVID-19. Lotz et al., for example, highlighted its potential to improve acute respiratory distress syndrome in COVID-19.

However, SaNOtize’s clinical trial results suggest that it has a much earlier antiviral role against COVID-19. We will discuss the exact mechanism behind this in this report [1].

Main text

Protease is critical to determine the viral load of COVID-19

Furin is a member of the PCSK (pro-protein convertase subtilizing/Kexin) family. Furin is a type 1 membrane-bound protease utilized by multiple pathogens including human immune deficiency virus (HIV), Ebola virus, Marburg virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and even some bacterial toxins. Pathogenicity can increase several folds once they react with Furin and other pro-protein convertases. After Furin is cleaved, latent precursor proteins are activated. Hence, Furin-dependent infections may respond to therapeutics targeting host cell Furin [2].

The spike protein of SARS-CoV-2 is the cleavage site of Furin. It plays an essential role in the pathogenesis, host range, and infectivity of the virus. Furin requires a polybasic instead of a monobasic cleavage site. Hence, cleavage occurs at the junction of the two polybasic, spike protein subunits (S1 and S2). High virulence and low virulence influenza strains have different pathogenicities and are an excellent example of the relationship between viral pathogenicity and cleavage sites [3].

Nitric oxide is an inhibitor of viral proteases and subsequently of viral replication

Previous studies have noted that the antiviral role of nitric oxide is due to its inhibition of viral protease activity. It also prohibits viral replication. In a study, several viruses demonstrated the mechanism behind this phenomenon. These included coxsackievirus, picornaviruses, hantavirus, herpesvirus, rhinovirus, Japanese encephalitis, vaccinia, retrovirus, and many more (Table 1 exposes the clinical and laboratory trials which used NO as an antiviral agent) [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24].

Table 1 Review of in vivo and in vitro studies of the antiviral effect of nitric oxide

Nitric oxide inhibits viral protease activity by decreasing intracellular cations

Furin is a cellular protease enzyme expressed from the FURIN gene in humans. Furin shows an intriguing interplay between intracellular ions, especially cations. Potassium ions are the most common intracellular ions in our bodies, followed by magnesium—which can activate Furin directly. Molloy et al. noted that the intracellular calcium level noticeably influences the activity of Furin. Thus, Furin is a calcium-dependent enzyme [25].

Yamada and colleagues further supported the relationship between Furin and calcium levels. Inhibiting Furin prevented further neuronal damage caused by calcium influx after hypoxic injury [26]. Hence, impeding calcium channels can be a promising approach against Furin-activated organisms. Additionally, Li et al. stated in 2019 that calcium channel blockers (CCB) decrease the intensity of fever spikes and the occurrence of thrombocytopenia syndrome, categorized by manifestations of tick-borne hemorrhagic fever [27].

Nitric oxide encourages calcium efflux from cells, leading to decreased intracellular calcium levels. Van Hove et al. demonstrated this and proved that nitric oxide stimulates smooth muscle cells (SMCs) to relax directly or indirectly by decreasing the elevated calcium level [28]. As such, nitric oxide could inhibit Furin’s action by decreasing cytosolic levels of calcium.

Inhaled nitric oxide as post-exposure prophylaxis

Argyropoulos et al. concluded that a diagnostic viral load has no prognostic value [29]. While in a more recent report, Silva et al. found the saliva viral loads to be significantly higher in patients with chronic respiratory conditions, cardiovascular conditions, kidney disease, and diseases that compromise the immune system [30]. Patients with four or more risk factors had much higher saliva viral loads than patients with fewer risk factors, as did male patients. However, there was no relation between nose and throat viral loads and risk factors. Saliva viral loads were also higher in patients with worse clinical outcomes. As such, early interruption of viral replication in the upper respiratory tract might abort the development of significant symptoms and complications. This rationale might have led to the current inclusion criteria of SaNOtize’s ongoing clinical trial, which involves administration of the intranasal medication within 48 h of a diagnosis. SaNOtize could potentially be administered to medical personnel as post-exposure chemoprophylaxis.

Conclusion

Early reports of the role of nitric oxide in the treatment of COVID-19 suggested its use for the treatment of established acute respiratory distress syndrome. However, nitric oxide seems to have a much earlier and more efficient prophylactic role. It inhibits Furin, a protease needed for canonical viral replication of SARS-CoV-2, by decreasing cytosolic calcium levels. This action can prevent the exponential increase of viral load in the upper respiratory tract leading to the abortion of clinically symptomatic infection and subsequent complications. Nitric oxide could be a tool for post-exposure chemoprophylaxis in the at-risk groups, especially medical personnel.

Figure 1 summarizes the antiviral effect of nitric oxide and its possible uses in the context of COVID-19.

Fig. 1
figure1

Inhaled NO for chemoprophylaxis of COVID-19. Abbreviations: COVID-19, coronavirus 2019; NO, nitric oxide; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2

Availability of data and materials

Not applicable

Abbreviations

CCB:

Calcium channel blocker

COVID-19:

Coronavirus 2019

NHS:

National Hospital System

NO:

Nitric oxide

NONS:

Nitric oxide nasal spray

SARS-CoV-2:

Severe acute respiratory syndrome coronavirus 2

UK:

United Kingdom

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Acknowledgements

To our families who are bearing the weight of our sacrifice of time to our patients. If our families were not understanding to the depth of our struggle, we would have never been able to keep the same level of dedication to our patients. To our students that we involve in each step of our researches to make them flourish in this field and take the lead the soonest the possible.

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This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

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AA, HI, AK, and ME contributed to the conception and design of the work. RF, YN, RH, MA, NE, and NK contributed significantly to the acquisition of data. AA, HI, AK, ME, RF, YN, RH, MA, NE, and NK contributed to the analysis and interpretation of data. AA, HI, AK, ME, RF, YN, RH, MA, NE, and NK contributed to the drafting and revision of the manuscript. All authors have approved the submitted version. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.

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Correspondence to Antoine AbdelMassih.

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AbdelMassih, A., Hozaien, R., El Shershaby, M. et al. The potential role of inhaled nitric oxide for postexposure chemoprophylaxis of COVID-19. J Genet Eng Biotechnol 19, 165 (2021). https://doi.org/10.1186/s43141-021-00249-5

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