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

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.

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) .

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.

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.
Authors' contributions 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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Competing interests
The authors declare that they have no competing interests.