# Peptides Derived from the SARS-CoV-2 S2-Protein Heptad-Repeat-2 Inhibit Pseudoviral Fusion at Micromolar Concentrations: The Role of Palmitic Acid Conjugation

## TL;DR

This study shows that a modified version of a SARS-CoV-2 protein-derived peptide can significantly reduce viral fusion at micromolar concentrations.

## Contribution

The novelty lies in demonstrating the inhibitory effect of a palmitoylated HR2-derived peptide on pseudoviral fusion.

## Key findings

- The palmitoylated HR2-derived peptide reduced fusion activity by 76% at 10 µM.
- Peptide derivatization and pseudovirus membrane composition affect inhibitory potency.
- Higher concentrations of peptide inhibitors may be needed for effective SARS-CoV-2 inhibition.

## Abstract

SARS-CoV-2 S-protein-mediated fusion is thought to involve the interaction of the membrane-distal or N-terminal heptad repeat (NHR) (“HR1”) of the cleaved S2 segment of the protein and the membrane-proximal or C-terminal heptad repeat (CHR) (“HR2”) regions of the protein. We examined the fusion inhibitory activity of a PEGylated HR2-derived peptide and its palmitoylated derivative using a pseudovirus infection assay. The latter peptide caused a 76% reduction in fusion activity at 10 µM. Our results suggest that small variations in peptide derivatization and differences in the membrane composition of pseudovirus preparations may affect the inhibitory potency of HR2-derived peptides. We suggest that future studies on the inhibition of infectivity of SARS-CoV-2 in both in vitro and in vivo systems consider the need for higher concentrations of peptide inhibitors.