First example of peptides targeting the dimer interface of Leishmania infantum trypanothione reductase with potent in vitro antileishmanial activity

A series of 9-mer and 13-mer amide-bridged cyclic peptides derived from the linear prototype Ac-PKIIQSVGIS-Nle-K-Nle-NH2 (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 o...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2017-07, Vol.135, p.49-59
Main Authors: Ruiz-Santaquiteria, Marta, Sánchez-Murcia, Pedro A., Toro, Miguel A., de Lucio, Héctor, Gutiérrez, Kilian Jesús, de Castro, Sonia, Carneiro, Filipa A.C., Gago, Federico, Jiménez-Ruiz, Antonio, Camarasa, María-José, Velázquez, Sonsoles
Format: Article
Language:English
Subjects:
Antiprotozoal Agents - chemical synthesis
Antiprotozoal Agents - chemistry
Antiprotozoal Agents - pharmacology
Cell Proliferation - drug effects
Cell-penetrating peptides
Cells, Cultured
Dimerization
Dose-Response Relationship, Drug
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Helix stabilization
Leishmania infantum
Leishmania infantum - cytology
Leishmania infantum - drug effects
Leishmania infantum - metabolism
Molecular Dynamics Simulation
Molecular Structure
NADH, NADPH Oxidoreductases - antagonists & inhibitors
NADH, NADPH Oxidoreductases - metabolism
Peptides
Peptides - chemical synthesis
Peptides - chemistry
Peptides - pharmacology
Protein-protein interactions
Structure-Activity Relationship
Trypanothione reductase
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Summary:A series of 9-mer and 13-mer amide-bridged cyclic peptides derived from the linear prototype Ac-PKIIQSVGIS-Nle-K-Nle-NH2 (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. [Display omitted] •Lactam-bridged peptides derived from linear prototypes are reported.•Potent inhibition of Li-TryR oxidoreductase activity and dimerization is described.•Increased proteolytic stability relative to the linear prototype is observed.•Conjugation with cell-penetrating peptides results in potent leishmanicidal activity.•The presence of the parent peptide sequence in conjugates is critical for activity.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2017.04.020