Compelling Evidence for the Activity of Antiviral Peptides against SARS-CoV-2

Abstract

Multiple outbreaks of epidemic and pandemic viral diseases have occurred in the last 20 years, including those caused by Ebola virus, Zika virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The emergence or re-emergence of such diseases has revealed the deficiency in our pipeline for the discovery and development of antiviral drugs. One promising solution is the extensive library of antimicrobial peptides (AMPs) produced by all eukaryotic organisms. AMPs are widely known for their activity against bacteria, but many possess additional antifungal, antiparasitic, insecticidal, anticancer, or antiviral activities. AMPs could therefore be suitable as leads for the development of new peptide-based antiviral drugs. Sixty therapeutic peptides had been approved by the end of 2018, with at least another 150 in preclinical or clinical development. Peptides undergoing clinical trials include analogs, mimetics, and natural AMPs. The advantages of AMPs include novel mechanisms of action that hinder the evolution of resistance, low molecular weight, low toxicity toward human cells but high specificity and efficacy, the latter enhanced by the optimization of AMP sequences. In this opinion article, we summarize the evidence supporting the efficacy of antiviral AMPs and discuss their potential to treat emerging viral diseases including COVID-19.

Keywords: COVID-19; SARS-CoV-2; antimicrobial peptides; antiviral peptides; coronavirus; defensins.

Figure 1

The four main structural classes of AMPs. (A) Clavavin adopts a typical α-helical conformation (10.2210/pdb6C41/pdb). (B) Protegrin PG-5 is a β-sheet peptide (10.2210/pdb2NC7/pdb). (C) Temporin B has a linear extension structure (10.2210/pdb6GIL/pdb). (D) Human β-defensin 1 features both α-helix and β-sheet structures (10.2210/pdb1IJV/pdb). The antiviral peptides were obtained from the Protein Data Bank (PDB) and adjustments were made using UCSF Chimera (http://www.cgl.ucsf.edu/chimera accessed on 22 April 2021).

Figure 2

Inhibition of SARS-CoV-2 infection by antiviral peptide P9. In a normal infection, the SARS-CoV-2 spike glycoprotein binds to host cell receptor ACE-2, allowing fusion with the host cell membrane. Antiviral peptide P9 binds to the surface of the spike glycoprotein and blocks its access to ACE-2, thus preventing fusion. The secondary structure of P9 was predicted using the Phyre2 protein modeling program [51].