Improved proteolytic stability and potent activity against Leishmania infantum trypanothione reductase of alfa/beta-peptide foldamers conjugated to cell-penetrating peptides

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 goa...

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Detalles Bibliográficos
Autores: Lucio Ortega, Héctor Elessar de|||0000-0002-9840-0779, Gamo, Ana María, Ruiz Santaquiteria, Marta, Castro de la Osa, Sonia de, Sánchez Murcia, Pedro Alejandro|||0000-0001-8415-870X, Toro Londoño, Miguel Ángel, Gutiérrez Viñas, Kilian Jesús, Gago Badenas, Federico|||0000-0002-3071-4878, Jiménez Ruiz, Antonio|||0000-0001-8238-3081, Camarasa Rius, María José, Velázquez Díaz, Sonsoles
Tipo de recurso: artículo
Fecha de publicación:2017
País:España
Institución:Universidad de Alcalá (UAH)
Repositorio:e_Buah Biblioteca Digital Universidad de Alcalá
Idioma:inglés
OAI Identifier:oai:ebuah.uah.es:10017/58997
Acceso en línea:http://hdl.handle.net/10017/58997
https://dx.doi.org/10.1016/j.ejmech.2017.09.032
Access Level:acceso abierto
Palabra clave:alpha/beta-Peptides
Foldamers
Proteolysis
Protein-protein interactions
Trypanothione reductase
Leishmania infantum
Medicina
Medicine
Descripción
Sumario: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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