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.
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