Peptidomimetic Small-Molecule Inhibitors of 3CLPro Activity and Spike-ACE2 Interaction: Toward Dual-Action Molecules against Coronavirus Infections.
J Org Chem
; 87(18): 12041-12051, 2022 09 16.
Article
in English
| MEDLINE | ID: covidwho-2016521
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Peptidomimetics
/
COVID-19
Limits:
Humans
Language:
English
Journal:
J Org Chem
Year:
2022
Document Type:
Article
Affiliation country:
Acs.joc.2c01047
Similar
MEDLINE
...
LILACS
LIS