Back to Search
Start Over
Synthesis, structure-activity relationship and antiviral activity of indole-containing inhibitors of Flavivirus NS2B-NS3 protease.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2021 Dec 05; Vol. 225, pp. 113767. Date of Electronic Publication: 2021 Aug 14. - Publication Year :
- 2021
-
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 IC <subscript>50</subscript> 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 EC <subscript>68</subscript> values of 1-3 μM. These compounds are novel pharmacological leads for further drug development targeting Zika virus.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Antiviral Agents chemical synthesis
Antiviral Agents chemistry
Dose-Response Relationship, Drug
Indoles chemical synthesis
Indoles chemistry
Microbial Sensitivity Tests
Molecular Structure
RNA Helicases antagonists & inhibitors
RNA Helicases metabolism
Serine Endopeptidases metabolism
Structure-Activity Relationship
Viral Nonstructural Proteins metabolism
Antiviral Agents pharmacology
Indoles pharmacology
Viral Nonstructural Proteins antagonists & inhibitors
Zika Virus drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 225
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34450494
- Full Text :
- https://doi.org/10.1016/j.ejmech.2021.113767