First example of peptides targeting the dimer interface of Leishmania infantum trypanothione reductase with potent in vitro antileishmanial activity
Authors
Ruiz Santaquiteria, Marta; Sánchez Murcia, Pedro Alejandro; Toro Londoño, Miguel Ángel; Lucio Ortega, Héctor Elessar de; Gutiérrez Viñas, Kilian Jesús; [et al.]Identifiers
Permanent link (URI): http://hdl.handle.net/10017/58953DOI: 10.1016/j.ejmech.2017.04.020
ISSN: ISSN: 0223-5234
Date
2017-07-28Affiliation
Universidad de Alcalá. Departamento de Ciencias Biomédicas; Universidad de Alcalá. Departamento de Biología de SistemasFunders
Ministerio de Economía y Competitividad
Comunidad de Madrid
Bibliographic citation
European Journal of Medicinal Chemistry, 2017, v. 135, p. 49-59
Keywords
Peptides
Helix stabilization
Protein-protein interactions
Trypanothione reductase
Leishmania infantum
Cell-penetrating peptides
Project
info:eu-repo/grantAgreement/CAM/S-2010/BMD-2457%2FBIPEDD-2-CM/ES/
info:eu-repo/grantAgreement/MINECO/SAF2012-39760-C02/ES/
info:eu-repo/grantAgreement/MINECO/SAF2015-64629-C2/ES/
Document type
info:eu-repo/semantics/article
Version
info:eu-repo/semantics/publishedVersion
Rights
© The Author(s), 2017
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Access rights
info:eu-repo/semantics/openAccess
Abstract
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. ChemBioChem 2013) 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.
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First_Ruiz_EuJMedChem_2017.pdf | 1.987Mb |
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