Potent Antiviral Activity against HSV-1 and SARS-CoV-2 by Antimicrobial Peptoids

Abstract

Viral infections, such as those caused by Herpes Simplex Virus-1 (HSV-1) and SARS-CoV-2, affect millions of people each year. However, there are few antiviral drugs that can effectively treat these infections. The standard approach in the development of antiviral drugs involves the identification of a unique viral target, followed by the design of an agent that addresses that target. Antimicrobial peptides (AMPs) represent a novel source of potential antiviral drugs. AMPs have been shown to inactivate numerous different enveloped viruses through the disruption of their viral envelopes. However, the clinical development of AMPs as antimicrobial therapeutics has been hampered by a number of factors, especially their enzymatically labile structure as peptides. We have examined the antiviral potential of peptoid mimics of AMPs (sequence-specific N-substituted glycine oligomers). These peptoids have the distinct advantage of being insensitive to proteases, and also exhibit increased bioavailability and stability. Our results demonstrate that several peptoids exhibit potent in vitro antiviral activity against both HSV-1 and SARS-CoV-2 when incubated prior to infection. In other words, they have a direct effect on the viral structure, which appears to render the viral particles non-infective. Visualization by cryo-EM shows viral envelope disruption similar to what has been observed with AMP activity against other viruses. Furthermore, we observed no cytotoxicity against primary cultures of oral epithelial cells. These results suggest a common or biomimetic mechanism, possibly due to the differences between the phospholipid head group makeup of viral envelopes and host cell membranes, thus underscoring the potential of this class of molecules as safe and effective broad-spectrum antiviral agents. We discuss how and why differing molecular features between 10 peptoid candidates may affect both antiviral activity and selectivity.

The Peptide A-3302-B Isolated from a Marine Bacterium Micromonospora sp. Inhibits HSV-2 Infection by Preventing the Viral Egress from Host Cells

“…No difference in viral titers of treated and control samples was observed, indicating that the compound did not exert intrinsic virucidal activity (Figure S7). This finding contrasted with many reports in the literature in which natural peptides showed direct inactivation of HSV particles by disrupting the viral envelope [37][38][39][40][41].…”

HD5 and LL-37 Inhibit SARS-CoV and SARS-CoV-2 Binding to Human ACE2 by Molecular Simulation

“…Depending on the action mechanism, recent studies have claimed that LL37, along with inactivating HSV-1, can be used as a therapeutic agent against SARS-CoV-2 [ 24 ]. Additionally, a new study found that LL37 attaches to the SARS-CoV-2 spike protein [ 25 ] instead of just attaching itself to the membrane.…”

HBD-2 binds SARS-CoV-2 RBD and blocks viral entry: Strategy to combat COVID-19

“…Detailed thermodynamics analyses, both experimental and computational are needed to clarify this point. Nevertheless, our work and that of others suggests that design of AMP-derived peptides and peptide mimetics could be a useful strategy in combating CoV-2 variants (Bakovic et al, 2021;Diamond et al, 2021;Zhang et al, 2021).…”