Peptide-Based Inhibitors of Protein-Protein Interactions (PPIs): A Case Study on the Interaction Between SARS-CoV-2 Spike Protein and Human Angiotensin-Converting Enzyme 2 (hACE2)

Abstract

Protein-protein interactions (PPIs) are fundamental to many critical biological processes and are crucial in mediating essential cellular functions across diverse organisms, including bacteria, parasites, and viruses. A notable example is the interaction between the SARS-CoV-2 spike (S) protein and the human angiotensin-converting enzyme 2 (hACE2), which initiates a series of events leading to viral replication. Interrupting this interaction offers a promising strategy for blocking or significantly reducing infection, highlighting its potential as a target for anti-SARS-CoV-2 therapies. This review focuses on the hACE2 and SARS-CoV-2 spike protein interaction, exemplifying the latest advancements in peptide-based strategies for developing PPI inhibitors. We discuss various approaches for creating peptide-based inhibitors that target this critical interaction, aiming to provide potential treatments for COVID-19.

Keywords: ACE2; COVID-19; SARS-CoV-2; angiotensin-converting enzyme 2; coronavirus; drug design; inhibitors of protein–protein interactions; peptides.

Figure 1

The complex structure of hACE2 and SARS-CoV-2 spike proteins (PDB id: 6m0j)— computer-generated, cartoon representation. (a) The interaction interface between hACE2 (blue) and the spike (orange) is shown as the solvent accessible surface area and highlighted by magenta and cyan colors, respectively; (b,c) depicted amino acid residues forming the interface for a particular protein are shown as sticks in this representation; (d) schematic diagram of interactions between proteins. Residues are colored according to the type: positive (H, K, R); negative (D, E); S, T, N, Q = neutral; A, V, L, I, M = aliphatic; F, Y, W = aromatic; G = Gly. Type of contacts: hydrogen bonds (blue line); salt bridges (red line); nonbonded contacts (gray dash line). Protein visualization was prepared by the PyMOL Molecular Graphics System, Version 3.0.0 Schrödinger, LLC.