In-silico drug repurposing study predicts the combination of pirfenidone and melatonin as a promising candidate therapy to reduce SARS-CoV-2 infection progression and respiratory distress caused by cytokine storm

Abstract

From January 2020, COVID-19 is spreading around the world producing serious respiratory symptoms in infected patients that in some cases can be complicated by the severe acute respiratory syndrome, sepsis and septic shock, multiorgan failure, including acute kidney injury and cardiac injury. Cost and time efficient approaches to reduce the burthen of the disease are needed. To find potential COVID-19 treatments among the whole arsenal of existing drugs, we combined system biology and artificial intelligence-based approaches. The drug combination of pirfenidone and melatonin has been identified as a candidate treatment that may contribute to reduce the virus infection. Starting from different drug targets the effect of the drugs converges on human proteins with a known role in SARS-CoV-2 infection cycle. Simultaneously, GUILDify v2.0 web server has been used as an alternative method to corroborate the effect of pirfenidone and melatonin against the infection of SARS-CoV-2. We have also predicted a potential therapeutic effect of the drug combination over the respiratory associated pathology, thus tackling at the same time two important issues in COVID-19. These evidences, together with the fact that from a medical point of view both drugs are considered safe and can be combined with the current standard of care treatments for COVID-19 makes this combination very attractive for treating patients at stage II, nonsevere symptomatic patients with the presence of virus and those patients who are at risk of developing severe pulmonary complications.

Commentary: Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused

“…The reason behind suggesting Pirfenidone is not simply the similarity of COVID-19 ARDS/Fibrosis and IPF; but the pathogenesis of COVID-19 disease; it's receptor, and the mechanism of action of Pirfenidone. In line with our hypothesis, a recent in-silico drug repurposing study suggested promising modeling results for the combination of Pirfenidone and melatonin as a potential treatment to diminish SARS-CoV-2 infection progression and respiratory distress due to cytokine storm ( 6 ). Nevertheless, at the end of the day, only clinical trials are going to determine if this hypothetical treatment would work.…”

Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions

“…There appears to be no standard approach to treating cytokine release syndromes that currently addresses all three, and the vast majority address none, focusing instead on antagonizing cytokine functions. However, melatonin (N-acetyl-5-methoxy tryptamine) has recently emerged as an effective therapy for severe COVID-19 [ 246 , 247 , 248 , 249 , 250 , 251 ]. While melatonin is often thought of being mainly a sleep regulator, it also has widespread effects on the innate immunity—in particular, antagonizing TLR2, TLR4, TLR9, NLRP3 and, possibly, NOD2 [ 59 , 252 , 253 , 254 , 255 ].…”

Artificial Intelligence-driven drug repurposing and structural biology for SARS-CoV-2

“…Artigas et al (Artigas et al 2020) utilized a systems biology and AI-based approach, the Therapeutic Performance Mapping System (TPMS) technology (Jorba et al 2020) to repurpose drugs and drug combinations for COVID-19. TPMS method employs an ANN to measure the potential relationship between the nodes of a network (i.e.…”