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Virology

. 2009 Dec 5;395(1):1-9.

doi: 10.1016/j.virol.2009.09.007. Epub 2009 Oct 1.

Dual Effect of Nitric Oxide on SARS-CoV Replication: Viral RNA Production and Palmitoylation of the S Protein Are Affected

Sara Akerström¹, Vithiagaran Gunalan, Choong Tat Keng, Yee-Joo Tan, Ali Mirazimi

Affiliations expand

• PMID: 19800091
• PMCID: PMC7111989
• DOI: 10.1016/j.virol.2009.09.007

Free PMC article

Abstract

Nitric oxide is an important molecule playing a key role in a broad range of biological process such as neurotransmission, vasodilatation and immune responses. While the anti-microbiological properties of nitric oxide-derived reactive nitrogen intermediates (RNI) such as peroxynitrite, are known, the mechanism of these effects are as yet poorly studied. Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) belongs to the family Coronaviridae, was first identified during 2002-2003. Mortality in SARS patients ranges from between 6 to 55%. We have previously shown that nitric oxide inhibits the replication cycle of SARS-CoV in vitro by an unknown mechanism. In this study, we have further investigated the mechanism of the inhibition process of nitric oxide against SARS-CoV. We found that peroxynitrite, an intermediate product of nitric oxide in solution formed by the reaction of NO with superoxide, has no effect on the replication cycle of SARS-CoV, suggesting that the inhibition is either directly effected by NO or a derivative other than peroxynitrite. Most interestingly, we found that NO inhibits the replication of SARS-CoV by two distinct mechanisms.

• Firstly, NO or its derivatives cause a reduction in the palmitoylation of nascently expressed spike (S) protein which affects the fusion between the S protein and its cognate receptor, angiotensin converting enzyme 2.
• Secondly, NO or its derivatives cause a reduction in viral RNA production in the early steps of viral replication, and this could possibly be due to an effect on one or both of the cysteine proteases encoded in Orf1a of SARS-CoV.

UPDATED ON 4/21/2020

A Possible Explanation for the COVID-19 Racial Disparity

— And a possible solution

by Jason Kidde MS, MPAS, PA-C April 18, 2020

While the pathophysiology of hypertension is complex and multifaceted, there are notable racial differences. In the context of COVID-19, the most suspicious difference is a comparative deficiency of L-arginine and subsequently nitric oxide (NO). In this lies a potential explanation for the COVID-19 race disparity

NO is a gas synthesized by our cells and has multiple roles, but perhaps is best known for vascular dilation. In short, NO facilitates relaxation of vascular smooth muscle allowing vessel dilation and increased blood flow.

This on its own has potential implications in acute respiratory distress syndrome (ARDS), a condition that results from severe COVID-19 infection. By improving blood flow across the entire lung, this theoretically results in improved gas exchange and oxygenation of the blood. In fact, there is research that inhaled NO improved oxygenation and other clinical outcomes in SARS-1 patients, and current research in COVID-19 coronavirus (SARS-CoV-2) supports this previously demonstrated efficacy.

Additionally, abnormal blood clotting is an increasingly recognized complication of this disease, both systemically and within the pulmonary circulation. In fact, one of the greatest predictors of death is a serum blood test that indicates elevated clotting activity. Most recently, some physicians have suggested that small clots within the lungs are central to pathogenesis and have administered clot busting drugs known as thrombolytics which abruptly improve oxygenation, albeit transiently, as the medication effect weans and the predisposition to clot formation persists. NO inhibits clot formation, and deficiency may contribute to a prothrombotic state. In fact, it has been shown that inhaled NO decreases the propensity of clotting in ARDS.

However, perhaps the most convincing role of nitric oxide in this disease is its antiviral properties. SARS-CoV-2 infects cells by attaching to a receptor on the lining of the airways called angiotensin-converting enzyme 2 (ACE2). This is the same mechanism by which SAR-1 infects cells. NO specifically alters a surface protein on SARS-1, known as the spike protein, such that it cannot attach to the ACE2 receptor. This results in blocking viral entry into the cell as well as the subsequent replication of the virus. Since SARS-CoV-2 shares the same mechanism of cell entry, we can relatively confidently assume that NO would have a similar effect regarding this novel virus.

Knowing that NO deficiency is common in African Americans and that this population is disproportionately dying from an infection that can be blocked by this gas, augmenting NO seems like a reasonable therapeutic target. While NO is being used as an inhaled gas via mechanical ventilation, this is only suitable for someone ill enough to require mechanical ventilation.

A better way to increase nitric oxide in the minimally ill or even uninfected is to augment the body’s ability to create it. There are many pharmacologic ways to do this; however, potentially the most effective, cheapest, and lowest risk is to supplement with the precursor amino-acids L-arginine and L-citrulline. We already know these nutritional supplements result in this very effect and that there seems to be a more potent effect of supplementation on NO production in L-arginine-deficient African Americans.

Therefore, a reasonable action is to expedite clinical trials to further investigate this theory. At a minimum, we need to start a conversation to improve our understanding of the role of nitric oxide deficiency as a risk factor for disease severity. It is my strong belief that augmenting NO via L-arginine and L-citrulline not only has potential for treatment and reducing progression to severe illness, but given the safety profile, it may be most valuable as a preventative measure.

It could save many lives at a minimal cost.

Jason Kidde, MS, MPAS, is a physician assistant at University of Utah Health in Salt Lake City.

Last Updated April 21, 2020

ummary: A new clinical trial is enrolling patients with severe COVID-19 symptoms to assess the effect of nitric oxide in treating the virus. Previous research found nitric oxide has antiviral properties against coronaviruses. The effect was tested and demonstrated during the SARS outbreak in the early 2000s.

Source: University of Alabama at Birmingham

The University of Alabama at Birmingham has been selected to begin enrolling patients in an international study assessing the use of inhaled nitric oxide (iNO) to improve outcomes for COVID-19 patients with severely damaged lungs.

iNO has been used for the treatment of failing lungs, but it was also found to have antiviral properties against coronaviruses

“In humans, nitric oxide is generated within the blood vessels and regulates blood pressure, and prevents formation of clots and also destroys potential toxins,” Arora said.

The UAB team says this pandemic has led to an extraordinary unifying response by the medical community, including ICU physicians, nurses, respiratory therapists, clinical trial specialists, reviewers and medical administrators, allowing for faster than normal approvals for potentially lifesaving research studies.

“The fact that we are able to get this trial started quickly was due to collaborations across specialties and fields of expertise at UAB with the common goal of providing the highest quality of scientifically proven care for our COVID-19 patients,” Arora said. “We are all trying to fight this together, and I hope, with our resilience, we shall overcome these difficult times.”

Other related articles published in this Open Access Online Scientific Journal include the following:

• Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use of iNO in the Institutional Market, Therapy Demand and Cost of Care vs. Existing Supply Solutions

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/03/clinical-indications-for-use-of-inhaled-nitric-oxide-ino-in-the-adult-patient-market-clinical-outcomes-after-use-therapy-demand-and-cost-of-care/

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