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First example of peptides targeting the dimer interface of Leishmania infantum trypanothione reductase with potent in vitro antileishmanial activity .
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2017 Jul 28; Vol. 135, pp. 49-59. Date of Electronic Publication: 2017 Apr 13. - Publication Year :
- 2017
-
Abstract
- A series of 9-mer and 13-mer amide-bridged cyclic peptides derived from the linear prototype Ac-PKIIQSVGIS-Nle-K-Nle-NH <subscript>2</subscript> (Toro et al. ChemBioChem2013) has been designed and synthesized by introduction of the lactam between amino acid side chains that are separated by one helical turn (i, i+4). All of these compounds were tested in vitro as both dimerization and enzyme inhibitors of Leishmania infantum trypanothione reductase (Li-TryR). Three of the 13-mer cyclic peptide derivatives (3, 4 and 6) inhibited the oxidoreductase activity of Li-TryR in the low micromolar range and they also disrupted enzyme dimerization. Cyclic analogues 3 and 4 were more resistant to proteases than was the linear prototype. Furthermore, the most potent TryR inhibitors in the linear and cyclic series displayed potent in vitro activity against Leishmania infantum upon conjugation with cationic cell-penetrating peptides. To date, these conjugated peptides can be considered the first example of TryR dimerization inhibitors that are active in cell culture.<br /> (Copyright © 2017 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Subjects :
- Antiprotozoal Agents chemical synthesis
Antiprotozoal Agents chemistry
Cell Proliferation drug effects
Cells, Cultured
Dimerization
Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Leishmania infantum cytology
Leishmania infantum metabolism
Molecular Dynamics Simulation
Molecular Structure
NADH, NADPH Oxidoreductases metabolism
Peptides chemical synthesis
Peptides chemistry
Structure-Activity Relationship
Antiprotozoal Agents pharmacology
Enzyme Inhibitors pharmacology
Leishmania infantum drug effects
NADH, NADPH Oxidoreductases antagonists & inhibitors
Peptides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 135
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28431354
- Full Text :
- https://doi.org/10.1016/j.ejmech.2017.04.020