Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Abstract

The relentless, protracted evolution of the SARS-CoV-2 virus imposes tremendous pressure on herd immunity and demands versatile adaptations by the human host genome to counter transcriptomic and epitranscriptomic alterations associated with a wide range of short- and long-term manifestations during acute infection and post-acute recovery, respectively. To promote viral replication during active infection and viral persistence, the SARS-CoV-2 envelope protein regulates host cell microenvironment including pH and ion concentrations to maintain a high oxidative environment that supports template switching, causing extensive mitochondrial damage and activation of pro-inflammatory cytokine signaling cascades. Oxidative stress and mitochondrial distress induce dynamic changes to both the host and viral RNA m6A methylome, and can trigger the derepression of long interspersed nuclear element 1 (LINE1), resulting in global hypomethylation, epigenetic changes, and genomic instability. The timely application of melatonin during early infection enhances host innate antiviral immune responses by preventing the formation of “viral factories” by nucleocapsid liquid-liquid phase separation that effectively blockades viral genome transcription and packaging, the disassembly of stress granules, and the sequestration of DEAD-box RNA helicases, including DDX3X, vital to immune signaling. Melatonin prevents membrane depolarization and protects cristae morphology to suppress glycolysis via antioxidant-dependent and -independent mechanisms. By restraining the derepression of LINE1 via multifaceted strategies, and maintaining the balance in m6A RNA modifications, melatonin could be the quintessential ancient molecule that significantly influences the outcome of the constant struggle between virus and host to gain transcriptomic and epitranscriptomic dominance over the host genome during acute infection and PASC.

Role of Melatonin in Viral, Bacterial and Parasitic Infections

“…However, in spite of this outsized number of publications, it is difficult to draw any definite conclusion about the therapeutic efficacy of MLT in COVID-19 patients. In fact, there are reports showing the positive therapeutic effect of exogenous MLT [ 67 , 68 , 69 , 70 , 71 , 72 ], while others deny any effect [ 73 , 74 , 75 ]. Amid the beneficial effects exerted by MLT against COVID-19, we can find the prevention of complications and reduction in mortality in severely ill patients [ 69 , 72 ], improvement in respiratory symptoms via the reduction in the lungs’ involvement [ 71 ] and reduced requirement for invasive mechanical ventilation, as well as overall improvement in clinical status [ 72 ].…”

“…Perhaps this drastic discrepancy is due to the wide array of doses and treatment schedules used in these studies which continue to perpetuate misconceptions about the real therapeutic properties of MLT. For example, MLT has been administered once per day in the evening at a 10 mg dose for 14 days [ 69 ] or twice per day without mentioning the timetable at a dose-pro-dose of 3 mg [ 69 ] or 5 mg [ 70 ] in these studies. In the rationale of the studies, no authors considered a possible distinction between the circadian and non-circadian effects of MLT that could be related to its conceivable therapeutic effect against SARS-CoV-2.…”

Light, Water, and Melatonin: The Synergistic Regulation of Phase Separation in Dementia

“…These nomenclatures are excellent illustrations of some of the broad-based metabolic effects achieved by melatonin as it regulates fundamental phase separation processes in living organisms. The role of melatonin in the regulation of phase separation in the context of neurodegenerative disorders, cancer multidrug resistance, and viral phase separation are clearly defined in several in-depth reviews [ 230 , 235 , 236 ]. Due to a limitation of scope, the reader may review these extensive discussions for a better understanding of molecular mechanisms employed by melatonin in the regulation of phase separation under different biological contexts.…”

Assessing the antiviral potential of melatonin: A comprehensive systematic review

“…The COVID‐19 pandemic, with its devastating impact on global health, spurred urgent research into repurposing existing drugs. Melatonin, with its well‐established safety profile and accessible availability, attracted attention as a potential adjunctive therapy for COVID‐19 7–11 . Preliminary evidence suggests that melatonin may play a multifaceted role in combating the virus, including inhibiting viral replication, mitigating excessive inflammation, and enhancing immune response.…”

“…Melatonin, with its well-established safety profile and accessible availability, attracted attention as a potential adjunctive therapy for COVID-19. [7][8][9][10][11] Preliminary evidence suggests that melatonin may play a multifaceted role in combating the virus, including inhibiting viral replication, mitigating excessive inflammation, and enhancing immune response. However, despite promising findings, the true extent of melatonin's antiviral efficacy and its potential application in the broader context of viral infections require further exploration.…”