Publication Date
3-11-2021
Journal
Journal of Medicinal Chemistry
DOI
10.1021/acs.jmedchem.0c02070
PMID
33596380
PMCID
PMC8052950
PubMedCentral® Posted Date
3-11-2022
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Allosteric Regulation, Animals, Antiviral Agents, Cell Line, Tumor, Dengue Virus, Humans, Mice, Molecular Structure, Pyrazines, Serine Endopeptidases, Serine Proteinase Inhibitors, Structure-Activity Relationship, Viral Nonstructural Proteins, Viral Proteins, Virus Replication, West Nile virus, Zika Virus, Zika Virus Infection
Abstract
Flaviviruses, including Zika, dengue and West Nile virus, 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 screen 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 virus 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.
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Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Genomics Commons, Medical Genetics Commons, Medical Specialties Commons, Molecular Genetics Commons
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