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

18 April 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


receptor-binding domain
protein-protein interaction
organic synthesis
enzyme inhibition
ELISA assay

Supplementary materials

Supplementary Material
Copies of 1H and 13C NMR for 2-14 Copies of HPLC chromatogram of 15 and 16 Copies of 1H-ES and TOCSY-ES of 16 Inhibition curves of 15 and 16 on 3CLPro enzyme Inhibition curve of 16 on Spike-ACE2 interaction


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