Abstract
Most therapeutic strategies for the development of antiviral agents are designed based on targets specific to each virus. We examined the potential broad-spectrum activity of antimicrobial peptoids (AMPs) against two different viruses. AMPs are mimetics of antimicrobial peptides, which are sequence-specific N-substituted glycine oligomers, where their side chains are appended to the backbone amide nitrogens rather than α-carbons. As a result, peptoids are not proteolyzed, and have improved biostability and bioavailability and reduced immunogenicity relative to natural peptides. AMPs exhibit potent in vitro activity against a wide variety of bacteria and fungi via disruption of microbial membranes as well intracellular binding to nucleic acids. Thus, we hypothesized that they also exhibit activity against enveloped viruses. HSV-1 is an enveloped DNA virus that causes topical lesions. Incubation of HSV-1 with a panel of AMPs demonstrates variable inactivation of the virus prior to infection of cultured epithelial cells. Peptoids with the best activity exhibited dose- and time-dependent inactivation of HSV-1. Lead compounds inactivate the virus within 30 minutes at µg/ml concentrations. Transmission electron microscopy shows that these compounds remove the viral envelope, similar to what is seen with detergent treatment. We also tested the compound against SARS-CoV-2, an enveloped RNA virus that causes COVID-19. Our results show a dose-dependent inactivation of this virus prior to infection of target cells. Cytotoxicity assays show little toxic effects when applied to the apical surface of well-differentiated air-liquid interface cultures of airway epithelial cells. These results indicate that AMPs are strong candidates for broad-spectrum antiviral agents.
Highlights
Antimicrobial peptides Broad-spectrum antimicrobial agents Cationic, amphipathic peptides Important components of innate immunity Mechanism of action is through membrane disruption Defensins, cathelicidins, protegrins, magainins
Goal: Design an antiviral drug based on antimicrobial peptides to target the viral envelope
Design novel antiviral molecules based on antimicrobial peptides
Summary
Traditional therapeutic strategies to treat pathogenic viruses involve designing drugs to target specific viral enzymes – Acyclovir for Herpes Simplex Virus (HSV)-1 – Resistance – Different drugs for each virus
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