Peptide–Boronic Acid Inhibitors of Flaviviral Proteases: Medicinal Chemistry and Structural Biology

A thousand-fold affinity gain is
achieved by introduction of a
C-terminal boronic acid moiety into dipeptidic inhibitors of the Zika,
West Nile, and dengue virus proteases. The resulting compounds have Ki values in the two-digit nanomolar range, are
not cytotoxic, and inhibit virus replication. Structure–activity
relationships and a high resolution X-ray cocrystal structure with
West Nile virus protease provide a basis for the design of optimized
covalent-reversible inhibitors aimed at emerging flaviviral pathogens.