Publication Date
12-5-2021
Journal
European Journal of Medicinal Chemistry
DOI
10.1016/j.ejmech.2021.113767
PMID
34450494
PMCID
PMC8585718
PubMedCentral® Posted Date
12-5-2022
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Antiviral Agents, Dose-Response Relationship, Drug, Indoles, Microbial Sensitivity Tests, Molecular Structure, RNA Helicases, Serine Endopeptidases, Structure-Activity Relationship, Viral Nonstructural Proteins, Zika Virus, Zika virus, Flavivirus, NS2B-NS3 protease, structure-activity relationship, antiviral
Abstract
Zika virus belongs to the Flavivirus family of RNA viruses, which include other important human pathogens such as dengue and West Nile virus. There are no approved antiviral drugs for these viruses. The highly conserved NS2B-NS3 protease of Flavivirus is essential for the replication of these viruses and it is therefore a drug target. Compound screen followed by medicinal chemistry optimization yielded a novel series of 2,6-disubstituted indole compounds that are potent inhibitors of Zika virus protease (ZVpro) with IC50 values as low as 320 nM. The structure-activity relationships of these and related compounds are discussed. Enzyme kinetics studies show the inhibitor 66 most likely exhibited a non-competitive mode of inhibition. In addition, this series of ZVpro inhibitors also inhibit the NS2B-NS3 protease of dengue and West Nile virus with reduced potencies. The most potent compounds 66 and 67 strongly inhibited Zika virus replication in cells with EC68 values of 1–3 μM. These compounds are novel pharmacological leads for further drug development targeting Zika virus.
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