Improved proteolytic stability and potent activity against Leishmania infantum trypanothione reductase of alfa/beta-peptide foldamers conjugated to cell-penetrating peptides
Authors
Lucio Ortega, Héctor Elessar de; Gamo , Ana María; Ruiz Santaquiteria, Marta; De Castro , Sonia; Sánchez Murcia, Pedro Alejandro; [et al.]Identifiers
Permanent link (URI): http://hdl.handle.net/10017/58997DOI: 10.1016/j.ejmech.2017.09.032
ISSN: 0223-5234
Date
2017-11-10Affiliation
Universidad de Alcalá. Departamento de Ciencias Biomédicas; Universidad de Alcalá. Departamento de Biología de SistemasFunders
Comunidad de Madrid
Ministerio de Economía y Competitividad
Bibliographic citation
European Journal of Medicinal Chemistry, 2017, v. 140, p. 615-623
Keywords
alpha/beta-Peptides
Foldamers
Proteolysis
Protein-protein interactions
Trypanothione reductase
Leishmania infantum
Project
info:eu-repo/grantAgreement/CAM/S-2010%2FBMD-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
© Elsevier Masson SAS, 2017
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Access rights
info:eu-repo/semantics/openAccess
Abstract
The objective of the current study was to enhance the proteolytic stability of peptide-based inhibitors that target critical protein-protein interactions at the dimerization interface of Leishmania infantum trypanothione reductase (Li-TryR) using a backbone modification strategy. To achieve this goal we carried out the synthesis, proteolytic stability studies and biological evaluation of a small library of ¿/ß3-peptide foldamers of different length (from 9-mers to 13-mers) and different ¿¿ß substitution patterns related to prototype linear ¿-peptides. We show that several 13-residue ¿/ß3-peptide foldamers retain inhibitory potency against the enzyme (in both activity and dimerization assays) while they are far less susceptible to proteolytic degradation than an analogous ¿-peptide. The strong dependence of the binding affinities for Li-TryR on the length of the ¿,ß-peptides is supported by theoretical calculations on conformational ensembles of the resulting complexes. The conjugation of the most proteolytically stable ¿/ß-peptide with oligoarginines results in a molecule with potent activity against L. infantum promastigotes and amastigotes.
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Improved_Lucio_EuJMedChem_2017.pdf | 1.896Mb |
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