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Potential therapeutic intervention of melatonin against COVID-19: A comparative pharmacokinetic study

Acharya et al., Melatonin Research, doi:10.32794/mr112500181

Dec 2024

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Melatonin for COVID-19

11th treatment shown to reduce risk in December 2020, now with p = 0.0000002 from 18 studies.

Lower risk for mortality, ventilation, and recovery.

No treatment is 100% effective. Protocols combine treatments.

5,200+ studies for 112 treatments. c19early.org

In Silico study showing that melatonin may be beneficial for COVID-19 compared to methylprednisolone, doxycycline, oseltamivir, and remdesivir. Authors find that melatonin has superior pharmacokinetic properties, including higher bioavailability, lipophilicity, and lack of P-glycoprotein substrate activity. Melatonin also targets more COVID-19 associated genes and has the highest number of enriched pathways, protein-protein interaction network nodes and edges, and average node degree compared to the other drugs. Molecular docking shows that melatonin substantially interacts with key COVID-19 related proteins including TP53, AKT1, IL6, TNF, IL1B, BCL2, EGFR, STAT3, CASP3, and NFKB1, suggesting it may modulate multiple aspects of COVID-19 pathology.

7 preclinical studies support the efficacy of melatonin for COVID-19:

3 In Silico studies1-3

1 In Vitro study4

3 In Vivo animal studies3,5,6

Melatonin may restore altered redox homeostasis in COVID-197, modulates type III interferon responses and reduces inflammatory cytokine production in TLR3 receptor agonist stimulated viral inflammation while preserving tissue integrity4, and negatively regulates genes critical for viral entry in lung tissue, including reduced expression of FURIN and components of the CD147 complex, while potentially disrupting TMPRSS2/ACE2-mediated entry mechanisms3. Melatonin reduces oxidative stress, inhibits NET formation, and protects tissues through anti-inflammatory and antioxidant actions8.

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1. Acharya et al., Potential therapeutic intervention of melatonin against COVID-19: A comparative pharmacokinetic study, Melatonin Research, doi:10.32794/mr112500181.melatonin-research.net, doi.org.

2. Kumar Yadalam et al., Assessing the therapeutic potential of angomelatine, ramelteon, and melatonin against SARS-Cov-2, Saudi Journal of Biological Sciences, doi:10.1016/j.sjbs.2022.01.049.sciencedirect.com, doi.org.

3. Fernandes et al., Melatonin-Index as a biomarker for predicting the distribution of presymptomatic and asymptomatic SARS-CoV-2 carriers, Melatonin Research, doi:10.32794/mr11250090.melatonin-research.net, doi.org.

4. Šeškutė et al., Antiviral Effect of Melatonin on Caco-2 Cell Organoid Culture: Trick or Treat?, International Journal of Molecular Sciences, doi:10.3390/ijms252211872.mdpi.com, doi.org.

5. Cecon et al., Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels, bioRxiv, doi:10.1101/2021.12.30.474561.biorxiv.org, doi.org.

6. Cecon (B) et al., Therapeutic potential of melatonin and melatonergic drugs on K18-hACE2 mice infected with SARS-CoV-2, Journal of Pineal Research, doi:10.1111/jpi.12772.wiley.com, doi.org.

7. Soto et al., Redox Homeostasis Alteration Is Restored through Melatonin Treatment in COVID-19 Patients: A Preliminary Study, International Journal of Molecular Sciences, doi:10.3390/ijms25084543.mdpi.com, doi.org.

8. Xie et al., The role of reactive oxygen species in severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection-induced cell death, Cellular & Molecular Biology Letters, doi:10.1186/s11658-024-00659-6.biomedcentral.com, doi.org.

Acharya et al., 31 Dec 2024, peer-reviewed, 2 authors. Contact: kazihasan5@gmail.com (corresponding author), kazi-nurul-hasan@skbu.ac.in.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Melatonin All

Potential therapeutic intervention of melatonin against COVID-19: A comparative pharmacokinetic study

Akash Acharyya, Kazi Nurul Hasan

Melatonin Research, doi:10.32794/mr112500181

Melatonin synthesis is primarily regulated by environmental light-dark cycle and is well known for its biological rhythm regulation and its potent antioxidant and anti-inflammatory properties across species. The present investigation focuses on the potential actions of melatonin as a therapeutic agent against COVID-19 and these actions are compared with other commonly used pharmacological agents of this kind including methylprednisolone, doxycycline, oseltamivir, and remdesivir. The comprehensive comparisons of pharmacokinetic profiles include their absorption, distribution, metabolism, and excretion (ADME) properties. The further in-depth analyses on their target identification, functional enrichment are performed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, construction of protein-protein interaction (PPI) networks, and molecular docking. These analyses elucidate the potential correlation of melatonin with critical hub targets implicated in COVID-19 pathogenesis. The results from pharmacokinetics indicates that melatonin has the higher bioavailability than the other tested drugs due to its low molecular weight, lipophilicity, lack of P-glycoprotein (P-gp) along with inhibitory action on cytochrome P450 1A2 (CYP1A2). GO and enriched KEGG analyses suggests that melatonin-mediated modulation of COVID-19 pathogenesis likely targets the AGE-RAGE pathway, HIF-1α signaling, and apoptosis. Furthermore, PPI network analysis also shows that melatonin has the highest nodes and edges, as well as the greatest average node degree score and highest common potential targets with the genes associated with the development of COVID-19. Notably, molecular docking study demonstrates the substantial interactions of melatonin with principal hub targets TP53, AKT1, IL6, TNF, IL1B, BCL2, EGFR, STAT3, CASP3, and NFKB1. Hence, melatonin has several significant pharmacokinetic advantages compared to selected therapeutic agents which may appear to modulate multiple facets of COVID-19 pathology. Based on the significant pharmacokinetic advantages of melatonin over the commonly used other drugs, the substantial clinical studies are necessary to establish its methods of application as a potential therapeutic against SARS-CoV-2 in the near future.

AUTHORSHIP AA conceptualized the experiment, set up methodologies, investigated and analysed data and written original draft. KNH supervised, acquired funding, conceptualized the experiment, set up methodologies, analyzed data, and performed writing-review & editing. CONFLICTS OF INTEREST The authors declare no conflicts of interest.

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