Mechanisms and clinical evidence to support melatonin's use in severe COVID-19 patients to lower mortality

Abstract

The fear of SARS-CoV-2 infection is due to its high mortality related to seasonal flu. To date, few medicines have been developed to significantly reduce the mortality of the severe COVID-19 patients, especially those requiring tracheal intubation. The severity and mortality of SARS-CoV-2 infection not only depend on the viral virulence, but are primarily determined by the cytokine storm and the destructive inflammation driven by the host immune reaction. Thus, to target the host immune response might be a better strategy to combat this pandemic. Melatonin is a molecule with multiple activities on a virus infection. These include that it downregulates the overreaction of innate immune response to suppress inflammation, promotes the adaptive immune reaction to enhance antibody formation, inhibits the entrance of the virus into the cell as well as limits its replication. These render it a potentially excellent candidate for treatment of the severe COVID-19 cases. Several clinical trials have confirmed that melatonin when added to the conventional therapy significantly reduces the mortality of the severe COVID-19 patients. The cost of melatonin is a small fraction of those medications approved by FDA for emergency use to treat COVID-19. Because of its self-administered, low cost and high safety margin, melatonin could be made available to every country in the world at an affordable cost. We recommend melatonin be used to treat severe COVID-19 patients with the intent of reducing mortality. If successful, it would make the SARS-CoV-2 pandemic less fearful and help to return life back to normalcy.

Keywords: Adaptive immunity; COVID-19; Inflammation; Innate immunity; Main protease; Melatonin; Nirmatrelvir; Ritonavir; SARS-CoV-2.

Fig. 1

The protective mechanisms of melatonin on SARS-CoV2 infection. Melatonin primarily targets the host to enhance the tolerance against pathogens. In addition, it may also target SARS-CoV-2 by blocking its entrance into cells and its replication. When the viral RNA is released into the cytoplasm and translated in two polyproteins (pp1a and pp1ab), both are cleaved by Mpro and papain-like protease (PLpro) to form 15 new non-structural proteins (nsps) that compose the replication-transcription complex. The newly formed RNA, nucleocapsid proteins and envelope glycoproteins assemble to form viral particles. Melatonin is an Mpro inhibitor and, thus can inhibit SARS CoV-2 replication. Red upward arrows: enhanced action; black downward arrows: reduced action; blue arrows: direction; red cross: blocking action; TMPRSS2: transmembrane protease serine 2; ACE2: angiotensin-converting enzyme 2, CD147: cluster of differentiation 147; Mpro: main protease. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)