Design and Structure-Activity Relationship of a Potent Furin Inhibitor Derived from Influenza Hemagglutinin

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-NH2 (CF1), based on the highly pathogenic avian influenza hemagglutinin. The goal of this study was to determine how its N-terminal part (the P8-PS 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 PS position with the small hydrophobic residues (Ile or Val) or a basic Lys.

Automated summary

The study aimed to improve the affinity of CF1 by altering its PS position. Results showed that substituting the PS position with small hydrophobic residues or a basic residue can enhance the activity of CF1.