Open AccessDesign and Structure–Activity Relationship of a Potent Furin Inhibitor Derived from Influenza Hemagglutinin
Author(s) -
Monika A Lewandowska-Goch,
Anna Kwiatkowska,
Teresa Łepek,
Kévin Ly,
Pauline Navals,
Hugo Gag,
Yves L. Dory,
Adam Prahl,
Robert Day
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00386
Subject(s) - furin , hemagglutinin (influenza) , peptide , structure–activity relationship , amino acid residue , amino acid , biology , virology , enzyme , influenza a virus , peptide sequence , computational biology , biochemistry , chemistry , virus , gene , in vitro
Furin plays an important role in various pathological states, especially in bacterial and viral infections. A detailed understanding of the structural requirements for inhibitors targeting this enzyme is crucial to develop new therapeutic strategies in infectious diseases, including an urgent unmet need for SARS-CoV-2 infection. Previously, we have identified a potent furin inhibitor, peptide Ac-RARRRKKRT- NH 2 (CF1), based on the highly pathogenic avian influenza hemagglutinin. The goal of this study was to determine how its N -terminal part (the P8-P5 positions) affects its activity profile. To do so, the positional-scanning libraries of individual peptides modified at the selected positions with natural amino acids were generated. Subsequently, the best substitutions were combined together and/or replaced by unnatural residues to expand our investigations. The results reveal that the affinity of CF1 can be improved (2-2.5-fold) by substituting its P5 position with the small hydrophobic residues (Ile or Val) or a basic Lys.