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

Nitric oxide (NO), a gaseous free radical produced from L-arginine catalyzed by NO synthase, functions as an important signaling molecule in the human body. Its antiviral activity was confirmed in the 1990s, and has been studied more extensively since the outbreak of the SARS pandemic in 2003. In the fight against the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, some recent studies have revealed the potential of NO in the treatment of coronavirus disease 2019 (COVID-19). The progress in this field, including several noteworthy clinical trials of inhaled NO for the treatment of COVID-19 and the emergency approval of NO nasal spray by the regulatory agencies of Israel, Bahrain, Thailand and Indonesia for the treatment of COVID-19 pneumonia, offers a new perspective for addressing the raging coronavirus infection and greatly broadens the clinical application of NO therapy. This review aims to explore the underlying molecular mechanisms of NO-based therapy against SARS-CoV-2, including direct viral inhibition, immune regulation, and protection against pulmonary and cardiovascular symptoms. Furthermore, the potential therapeutic applications of inhaled NO, NO donors and drugs involved in the NO pathway are discussed. In the context of a global vaccination campaign and newly proposed strategy of "coexistence with COVID-19," the advantages of NO therapies as symptomatic and adjuvant treatments are expected to deliver breakthroughs in the treatment of COVID-19.