Enfuvirtide, an HIV-1 fusion inhibitor peptide, can act as a potent SARS-CoV-2 fusion inhibitor: an in silico drug repurposing study

Abstract

Regarding the urgency of therapeutic measures for coronavirus disease 2019 (COVID-19) pandemic, the use of available drugs with FDA approval is preferred because of the less time and cost required for their development. In silico drug repurposing is an accurate way to speed up the screening of the existing FDA-approved drugs to find a therapeutic option for COVID-19. The similarity in SARS-CoV-2 and HIV-1 fusion mechanism to host cells can be a key point for Inhibit SARS-CoV-2 entry into host cells by HIV fusion inhibitors. Accordingly, in this study, an HIV-1 fusion inhibitor called Enfuvirtide (Enf) was selected. The affinity and essential residues involving in the Enf binding to the S2 protein of SARS-CoV-2, HIV-1 gp41 protein and angiotensin-converting enzyme 2 (ACE-2) as a negative control, was evaluated using molecular docking. Eventually, Enf-S2 and Enf-gp41 protein complexes were simulated by molecular dynamics (MD) in terms of binding affinity and stability. Based on the most important criteria such as docking score, cluster size, energy and dissociation constant, the strongest interaction was observed between Enf with the S2 protein. In addition, MD results confirmed that Enf-S2 protein interaction was remarkably stable and caused the S2 protein residues to undergo the fewest fluctuations. In conclusion, it can be stated that Enf can act as a strong SARS-CoV-2 fusion inhibitor and demonstrates the potential to enter the clinical trial phase of COVID-19.

Pan-coronavirus fusion inhibitors possess potent inhibitory activity against HIV-1, HIV-2, and simian immunodeficiency virus

“…The biophysical studies showed a significant interaction between T20 and a SARS-CoV HR1-derived peptide, suggesting that T20 could inhibit the fusion of SARS-CoV with the target cells but its effect is not strong enough for application [ 22 ]. Very recently, an in silico drug repurposing study showed that the interaction between T20 and SARS-CoV-2 S protein was remarkably stable and caused the S2 protein residues to undergo the fewest fluctuations, thus proposing T20 as potent SARS-CoV-2 fusion inhibitor with the potential to enter the clinical trial phase of COVID-19 [ 25 ]. However, the previous studies were primarily based on the bioinformatics approaches and lacked experimental evidence.…”

In silico design of quadruplex aptamers against the spike protein of SARS-CoV-2

“…By emerging of a global epidemic, many researchers sought to make it effective prevention and treatment strategies against COVID-19 using in silico , in vitro, and in vivo studies [ 25 ]. Regarding this pandemics, in silico methods have been used in different studies for analyzing the molecular structures of SARS-CoV-2 and even introducing potential therapeutic agents [ 26 , 27 ].…”

Recent progress in the development of potential drugs against SARS-CoV-2

“…It is well known that HR1 and HR2 both in S2 unit can interact with each other to form 6-HB, which helps to bring the viral and cellular membranes in close proximity for viral fusion/entry process ( Ahmadi et al, 2021 ). Therefore, they have become important target sites for inhibition against specific CoVs.…”