SAR evolution towards potent C-terminal carboxamide peptide inhibitors of Zika virus NS2B-NS3 protease.
Antiviral Agents
/ chemical synthesis
Dengue Virus
/ drug effects
Dose-Response Relationship, Drug
Humans
Microbial Sensitivity Tests
Molecular Structure
Peptides
/ chemical synthesis
Protease Inhibitors
/ chemical synthesis
RNA Helicases
/ antagonists & inhibitors
Serine Endopeptidases
/ metabolism
Structure-Activity Relationship
Viral Nonstructural Proteins
/ antagonists & inhibitors
West Nile virus
/ drug effects
Zika Virus
/ drug effects
Benzylamides
NS2B-NS3 protease
Non-covalent inhibitors
Peptide inhibitors
Peptidomimetic inhibitors
ZIKV
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
01 03 2022
01 03 2022
Historique:
received:
30
07
2021
revised:
12
01
2022
accepted:
13
01
2022
pubmed:
6
2
2022
medline:
22
3
2022
entrez:
5
2
2022
Statut:
ppublish
Résumé
Zika virus (ZIKV) is a member of the Flaviviridae family that can cause neurological disorders and congenital malformations. The NS2B-NS3 viral serine protease is an attractive target for the development of new antiviral agents against ZIKV. We report here a SAR study on a series of substrate-like linear tripeptides that inhibit in a non-covalent manner the NS2B-NS3 protease. Optimization of the residues at positions P1, P2, P3 and of the N-terminal and C-terminal portions of the tripeptide allowed the identification of inhibitors with sub-micromolar potency with phenylglycine as arginine-mimicking group and benzylamide as C-terminal fragment. Further SAR exploration and application of these structural changes to a series of peptides having a 4-substituted phenylglycine residue at the P1 position led to potent compounds showing double digit nanomolar inhibition of the Zika protease (IC
Identifiants
pubmed: 35123179
pii: S0968-0896(22)00023-2
doi: 10.1016/j.bmc.2022.116631
pii:
doi:
Substances chimiques
Antiviral Agents
0
NS2B protein, flavivirus
0
NS3 protein, flavivirus
0
Peptides
0
Protease Inhibitors
0
Viral Nonstructural Proteins
0
Serine Endopeptidases
EC 3.4.21.-
RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
116631Informations de copyright
Copyright © 2022 Elsevier Ltd. All rights reserved.