Open AccessSynthesis, Structure–Activity Relationships, and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B–NS3 Protease
Author(s) -
Shuang Nie,
Yuan Yao,
Feng Wu,
Xiaowei Wu,
Jidong Zhao,
Yilei Hua,
Jingyu Wu,
Tong Huo,
Yi-Lun Lin,
Alexander R. Kneubehl,
Megan B. Vogt,
Josephine C. Ferreon,
Rebeca Rico-Hesse,
Yuanlin Song
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c02070
Subject(s) - flavivirus , ns3 , zika virus , allosteric regulation , dengue virus , dengue fever , chemistry , virology , protease , viral replication , flaviviridae , structure–activity relationship , proteases , virus , biochemistry , biology , hepatitis c virus , in vitro , enzyme
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 IC 50 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 EC 68 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.