Covid-19 and L-arginine supplementations: Yet to find the missed key.

Current coronavirus disease (Covid-19) is regarded as a primary respiratory and vascular disease leading to acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and endothelial dysfunction (ED) in severe cases. The causative virus of Covid-19 is SARS-CoV-2, which binds angiotensin-converting enzyme 2 (ACE2) for its entry. It has been shown that ED is linked to various Covid-19 complications since endothelial cells are regarded as the chief barrier against SARS-CoV-2 invasion. SARS-CoV-2-indued ED leads to endotheliitis and thrombosis due to endothelial nitric oxide (NO) inhibition with subsequent vasoconstriction and tissue hypoxia. Loss of vasodilator NO and anti-thrombin factor from endothelial SARS-CoV-2 infection contribute to the progression of vascular dysfunction and coagulopathy. Therefore, NO restoration improves pulmonary function and hinders viral replication during respiratory viral infections, including Covid-19. L-arginine is a semiessential amino acid that has antiviral and immunomodulatory effects as well as it improves the biosynthesis of NO in endothelial cells. L-arginine may reduce risk of ALI through inhibition generation of peroxynitrite and suppression release of proinflammatory cytokines from alveolar macrophages. Of interest, restoration of NO by L-arginine may attenuate SARS-CoV-2 infection through different mechanisms, including reduction binding of SARS-CoV-2 to ACE2, inhibition of transmembrane protease serine type 2 (TMPRSS2) a critical for activation of SARS-CoV-2 spike protein and cellular entry, inhibition proliferation and replication of SARS-CoV-2, and prevention of SARS-CoV-2-induced coagulopathy. In conclusion, through antiviral and immunomodulatory effects, L-arginine and released NO have mutual and interrelated actions against SARS-CoV-2 infection.