Structure-Based Optimization and Characterization of Macrocyclic Zika Virus NS2B-NS3 Protease Inhibitors

Zika virus (ZIKV) is a human pathogenic
arbovirus. So far, neither
a specific treatment nor a vaccination against ZIKV infections has
been approved. Starting from our previously described lead structure,
a series of 29 new macrocyclic inhibitors of the Zika virus protease
containing different linker motifs have been synthesized. By selecting
hydrophobic d-amino acids as part of the linker, numerous
inhibitors with Ki values < 5 nM were
obtained. For 12 inhibitors, crystal structures in complex with the
ZIKV protease up to 1.30 Å resolution were determined, which
contribute to the understanding of the observed structure–activity
relationship (SAR). In immunofluorescence assays, an antiviral effect
was observed for compound 26 containing a d-homocyclohexylalanine
residue in its linker segment. Due to its excellent selectivity profile
and low cytotoxicity, this inhibitor scaffold could be a suitable
starting point for the development of peptidic drugs against the Zika
virus and related flaviviruses.