Peptidomimetic Small-Molecule Inhibitors of 3CLPro Activity and Spike–ACE2 Interaction: Toward Dual-Action Molecules against Coronavirus Infections

Abstract

The development of molecules able to target protein–protein interactions (PPIs) is of interest for the development of novel therapeutic agents. Since a high percentage of PPIs are mediated by α-helical structure at the interacting surface, peptidomimetics that reproduce the essential conformational components of helices are useful templates for the development of PPIs inhibitors. In this work, the synthesis of a constrained dipeptide isostere and insertion in the short peptide epitope EDLFYQ of the angiotensin-converting enzyme 2 (ACE2) α1 helix domain resulted in the identification of a molecule capable of inhibiting the SARS-CoV-2 ACE2/spike interaction in the micromolar range. Moreover, inhibition of SARS-CoV-2 3CLPro main protease activity was assessed as an additional inhibitory property of the synthesized peptidomimetics, taking advantage of the C-terminal Q amino acid present in both the ACE2 epitope and the Mpro recognizing motif (APSTVxLQ), thus paving the way to the development of multitarget therapeutics toward coronavirus infections.

Progress in Research on Inhibitors Targeting SARS-CoV-2 Main Protease (Mpro)

“…Other Inhibitors. By drawing on the development of molecules targeting protein−protein interactions (PPIs), Trabocchi's group 93 was able to develop a molecule capable of inhibiting SARS-CoV-2 ACE2/spiny interactions in the micromolar range, Compound 15 and Compound 16 (Figure 7D). It was obtained through the researchers' synthesis within a few steps using iminium chemistry.…”

Overview of Antiviral Drug Therapy for COVID-19: Where Do We Stand?

“…The unmistakable importance of the spike−ACE2 interaction in blocking viral replication prompted Tedesco et al to develop small molecules able to target protein−protein interactions. A pool of synthesized peptidomimetics were identified with a great inhibition power of the spike–ACE2 interaction, paving the way for the development of new therapeutics against coronavirus infections [ 83 ].…”

SARS‐CoV‐2 main protease inhibitors: What is moving in the field of peptides and peptidomimetics?

“…In a completely different approach, F. Tedesco and coworkers engineered an ACE2-derived peptide, EDLFYQ, through the incorporation of quite simple conformational restrictions in the middle of the molecule [44] . Minute modifications in the central restricted lactam allow the identification of peptidomimetics able to either inhibit SARS-CoV-2 Mpro (8, Figure 3, IC50 = 15 µM) or to interfere in the SARS-CoV-2 ACE2/spike interaction, while maintaining Some cyclic peptides have also been designed to bind main substrate pockets of the catalytic binding site of SARS-CoV-2 Mpro.…”

“…In a completely different approach, Tedesco et al engineered an ACE2-derived peptide, EDLFYQ, through the incorporation of quite simple conformational restrictions in the middle of the molecule. 44 Minute modifications in the central restricted lactam allow the identification of non-covalent peptidomimetics able to either inhibit SARS-CoV-2 Mpro (8; Figure 3, IC 50 = 15 μM) or to interfere in the SARS-CoV-2 ACE2/spike interaction, while maintaining inhibitory ability on the protease (compound 9; 3), which was designed through computational docking and molecular dynamics. 45 This cyclic peptide did not behave as a substrate of the SARS-CoV-2 Mpro but showed modest inhibitor activity (IC 50 = 160 μM).…”