English   español  
Por favor, use este identificador para citar o enlazar a este item: http://hdl.handle.net/10261/166587
Título

Trypanothione reductase inhibition and anti-leishmanial activity of all-hydrocarbon stapled α-helical peptides with improved proteolytic stability

AutorRuiz-Santaquiteria, Marta ; Castro, Sonia de ; Toro, Miguel A.; Lucio, Héctor de; Gutiérrez, Kilian Jesús; Sánchez-Murcia, Pedro A. ; Jiménez, María Angeles; Gago, Federico ; Jiménez-Ruiz, Antonio; Camarasa Rius, María José ; Velázquez, Sonsoles
Palabras claveStapled peptides
Leishmania infantum
Cell-penetrating peptides
Trypanothione reductase
Protein-protein interactions
Fecha de publicación2018
EditorElsevier
CitaciónEuropean Journal of Medicinal Chemistry 149: 238-247 (2018)
ResumenTrypanothione reductase (TryR) is a well-established target in the search for novel antitrypanosomal and antileishmanial agents. We have previously identified linear and lactam-bridged 13-residue peptides derived from an α-helical region making up part of the dimeric interface of Leishmania infantum TryR (Li-TryR) which prevent trypanothione reduction by disrupting enzyme dimerization. We now show that i,i + 4 side-chain cross-linking with an all-hydrocarbon staple stabilizes the helical structure of these peptides and significantly improves their resistance to protease cleavage relative to previous linear and cyclic lactam analogues. Interestingly, replacement of the amide bridge by the hydrocarbon staple at the same cyclization positions generates derivatives (2 and 3) that similarly inhibit oxidoreductase activity of the enzyme but unexpectedly stabilize the TryR homodimer. The most proteolytically stable peptide 2 covalently linked to oligoarginines displayed potent in vitro leishmanicidal activity against L. infantum parasites.
Versión del editorhttp://dx.doi.org/10.1016/j.ejmech.2018.02.071
URIhttp://hdl.handle.net/10261/166587
Identificadoresdoi: 10.1016/j.ejmech.2018.02.071
issn: 0223-5234
e-issn: 1768-3254
Aparece en las colecciones: (IQM) Artículos
(IQFR) Artículos
Ficheros en este ítem:
Fichero Descripción Tamaño Formato  
accesoRestringido.pdf15,38 kBAdobe PDFVista previa
Visualizar/Abrir
Mostrar el registro completo
 

Artículos relacionados:


NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.