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.
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.
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