Peptidomimetic small-molecule inhibitors of 3CLPro activity and Spike-ACE2 interaction: towards dual-action molecules against Coronavirus infections

The development of molecules able to target protein-protein interactions (PPIs) is of interest for the development of nov-el therapeutic agents. Since a high percentage of PPIs are mediated by α-helical structure at the interacting surface, pep-tidomimetics that reproduce the essential conformational components of helices are useful templates for the develop-ment of PPIs inhibitors. In this work, the synthesis of a constrained dipeptide isostere and insertion in the short peptide epitope EDLFYQ of the ACE2 α-helix 1 domain resulted in the identification of a molecule capable of inhibiting the SARS-CoV-2 ACE-2/Spike interaction in the micromolar range. Moreover, inhibition of SARS-CoV-2 3CLPro main protease activi-ty 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 recognising motif (APSTVxLQ), thus paving the way to the development of multitarget therapeutics towards Coronavirus infections.