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

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.