Melatonin, a hormone that regulates the sleep-wake cycle and is commonly used as an over-the-counter sleep aid, may be a viable treatment option for COVID-19, according to a US study in PLOS Biology.
As COVID-19 continues to spread throughout the world, particularly with cases rising during what some have termed the "fall surge," repurposing drugs already approved by the US Food and Drug Administration for new therapeutic purposes continues to be the most efficient and cost-effective approach to treat or prevent the disease. According to the findings published today in PLOS Biology, a novel artificial intelligence platform developed by Lerner Research Institute researchers to identify possible drugs for COVID-19 repurposing has revealed melatonin as a promising candidate.
Analysis of patient data from Cleveland Clinic's COVID-19 registry also revealed that melatonin usage was associated with a nearly 30 percent reduced likelihood of testing positive for SARS-CoV-2 (the virus that causes COVID-19) after adjusting for age, race, smoking history and various disease comorbidities. Notably, the reduced likelihood of testing positive for the virus increased from 30 to 52 percent for African Americans when adjusted for the same variables.
"It is very important to note these findings do not suggest people should start to take melatonin without consulting their physician," said Feixiong Cheng, PhD, assistant staff in Cleveland Clinic's Genomic Medicine Institute and lead author on the study. "Large-scale observational studies and randomised controlled trials are critical to validate the clinical benefit of melatonin for patients with COVID-19, but we are excited about the associations put forth in this study and the opportunity to further explore them."
Here, the researchers harnessed network medicine methodologies and large-scale electronic health records to identify clinical manifestations and pathologies common between COVID-19 and other diseases. Specifically, they measured the proximity between host genes/proteins and those well-associated with 64 other diseases across several disease categories (malignant cancer and autoimmune, cardiovascular, metabolic, neurological and pulmonary diseases), where closer proximity indicates a higher likelihood of pathological associations between the diseases.
They found, for example, that proteins associated with respiratory distress syndrome and sepsis, two main causes of death in patients with severe COVID-19, were highly connected with multiple SARS-CoV-2 proteins. "This signals to us, then," explained Dr Cheng, "that a drug already approved to treat these respiratory conditions may have some utility in also treating COVID-19 by acting on those shared biological targets."
Overall, they determined that autoimmune (e.g., inflammatory bowel disease), pulmonary (e.g., chronic obstructive pulmonary disease and pulmonary fibrosis) and neurological (e.g., depression and attention-deficit hyperactivity disorder) diseases showed significant network proximity to SARS-CoV-2 genes/proteins and identified 34 drugs as repurposing candidates, melatonin chief among them.
"Recent studies suggest that COVID-19 is a systematic disease impacting multiple cell types, tissues and organs, so knowledge of the complex interplays between the virus and other diseases is key to understanding COVID-19-related complications and identifying repurposable drugs," said Dr Cheng. "Our study provides a powerful, integrative network medicine strategy to predict disease manifestations associated with COVID-19 and facilitate the search for an effective treatment."
Abstract
The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of coexisting medical conditions, while the underlying mechanisms remain unclear. Furthermore, there are no approved therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, disease manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus–host protein–protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measurement revealed underlying pathogenesis for broad COVID-19-associated disease manifestations. Analyses of single-cell RNA sequencing data show that co-expression of ACE2 and TMPRSS2 is elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn disease patients compared to uninflamed tissues, revealing shared pathobiology between COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicate that COVID-19 shares an intermediate inflammatory molecular profile with asthma (including IRAK3 and ADRB2). To prioritize potential treatments, we combined network-based prediction and a propensity score (PS) matching observational study of 26,779 individuals from a COVID-19 registry. We identified that melatonin usage (odds ratio [OR] = 0.72, 95% CI 0.56–0.91) is significantly associated with a 28% reduced likelihood of a positive laboratory test result for SARS-CoV-2 confirmed by reverse transcription–polymerase chain reaction assay. Using a PS matching user active comparator design, we determined that melatonin usage was associated with a reduced likelihood of SARS-CoV-2 positive test result compared to use of angiotensin II receptor blockers (OR = 0.70, 95% CI 0.54–0.92) or angiotensin-converting enzyme inhibitors (OR = 0.69, 95% CI 0.52–0.90). Importantly, melatonin usage (OR = 0.48, 95% CI 0.31–0.75) is associated with a 52% reduced likelihood of a positive laboratory test result for SARS-CoV-2 in African Americans after adjusting for age, sex, race, smoking history, and various disease comorbidities using PS matching. In summary, this study presents an integrative network medicine platform for predicting disease manifestations associated with COVID-19 and identifying melatonin for potential prevention and treatment of COVID-19.
[link url="https://www.lerner.ccf.org/news/details/?Cleveland+Clinic+Researchers+Use+“Big+Data”+Approach+to+Identify+Melatonin+as+Possible+COVID-19+Treatment&368b40ada56204bc8992942e8032bedb4d865564&390f8e37ac9d0069b5928b94dac2d4a31f491013"]Cleveland Clinic materials[/link]
[link url="https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000970"]Full study in PLOS Biology (Open Access)[/link]