Synthesis, Structure–Activity Relationships, and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B–NS3 Protease

Flaviviruses,
including Zika, dengue, and West Nile viruses, are
important human pathogens. The highly conserved NS2B–NS3 protease
of Flavivirus is essential for viral replication and therefore a promising
drug target. Through compound screening, followed by medicinal chemistry
studies, a novel series of 2,5,6-trisubstituted pyrazine compounds
are found to be potent, allosteric inhibitors of Zika virus protease
(ZVpro) with IC50 values as low as 130 nM. Their structure–activity
relationships are discussed. The ZVpro inhibitors also inhibit homologous
proteases of dengue and West Nile viruses, and their inhibitory activities
are correlated. The most potent compounds 47 and 103 potently inhibited Zika virus replication in cells with
EC68 values of 300–600 nM and in a mouse model of
Zika infection. These compounds represent novel pharmacological leads
for drug development against Flavivirus infections.