Abstract

The COVID-19 pandemic has evidenced the urgent need for the discovery of broad-spectrum antiviral therapies that could be deployed in the case of future emergence of novel viral threats, as well as to back up current therapeutic options in the case of drug resistance development. Most current antivirals are directed to inhibit specific viruses since these therapeutic molecules are designed to act on a specific viral target with the objective of interfering with a precise step in the replication cycle. Therefore, antimicrobial peptides (AMPs) have been identified as promising antiviral agents that could help to overcome this limitation and provide compounds able to act on more than a single viral family. We evaluated the antiviral activity of an amphibian peptide known for its strong antimicrobial activity against both Gram-positive and Gram-negative bacteria, namely Temporin L (TL). Previous studies have revealed that TL is endowed with widespread antimicrobial activity and possesses marked haemolytic activity. Therefore, we analyzed TL and a previously identified TL derivative (Pro3, DLeu9 TL, where glutamine at position 3 is replaced with proline, and the D-Leucine enantiomer is present at position 9) as well as its analogs, for their activity against a wide panel of viruses comprising enveloped, naked, DNA and RNA viruses. We report significant inhibition activity against herpesviruses, paramyxoviruses, influenza virus and coronaviruses, including SARS-CoV-2. Moreover, we further modified our best candidate by lipidation and demonstrated a highly reduced cytotoxicity with improved antiviral effect. Our results show a potent and selective antiviral activity of TL peptides, indicating that the novel lipidated temporin-based antiviral agents could prove to be useful additions to current drugs in combatting rising drug resistance and epidemic/pandemic emergencies.

Highlights

  • One of the biggest public health challenges is emerging viral infections due to possible epidemic and pandemic risks

  • Gram-negative bacteria present an outer membrane surrounding the peptidoglycan shell, and despite the peculiar differences between outer membranes (OMs) and other biological membranes, our reasoning was that these two particular temporins may be more effective against lipid membranes, and able to affect enveloped viruses

  • The fatty acids conjugated-TL6 peptides were tested in cytotoxicity assays and inhibition assays with the following viruses: HSV-1, SARS-CoV-2, MeV and influenza virus, and the results showed an increase of the activity compared to the parent peptide up to 50-fold (Tables 6 and 7)

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Summary

Introduction

One of the biggest public health challenges is emerging viral infections due to possible epidemic and pandemic risks. In consideration of the current COVID-19 pandemic, it is unlikely that the traditional virus-specific paradigm of antiviral drug development can be implemented for the immediate availability of drugs, but it is essential to act promptly and effectively against new pathogens that cause unexpected but lethal infections. Within this perspective, the one-drug-to-one-target paradigm for antiviral drug discovery has proved inadequate for responding to an increasing diversity of viruses deadly in humans

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