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

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journal contribution
posted on 05.02.2021, 13:07 by Monika A. Lewandowska-Goch, Anna Kwiatkowska, Teresa Łepek, Kévin Ly, Pauline Navals, Hugo Gagnon, Yves L. Dory, Adam Prahl, Robert Day
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–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.