Issue 69, 2015

Comparison of hydrocarbon-and lactam-bridged cyclic peptides as dimerization inhibitors of Leishmania infantum trypanothione reductase

Abstract

All-hydrocarbon and lactam-bridged staples linking amino acid side-chains have been used to stabilize the α-helical motif in short 13-mer peptides that target critical protein–protein interactions at the dimerization interface of Leishmania infantum trypanothione reductase (Li-TryR). The design of the best positions for covalent hydrocarbon closure relied on a theoretical prediction of the degree of helicity of the corresponding cyclic peptides in water. Selected (i, i + 4) and (i, i + 7) hydrocarbon-stapled peptides were prepared by using solid-phase synthesis protocols and optimized ring-closing metathesis reactions under microwave conditions. Structural analysis by NMR spectroscopy confirmed high helical contents in aqueous TFE solutions for both types of helix-constrained cyclic peptides. Remarkably, the ability to prevent Li-TryR dimerization was reduced in both (i, i + 4) and (i, i + 7) hydrocarbon stapled peptides but was retained in the corresponding (i, i + 4) Glu–Lys lactam-bridged analogue, which also showed a higher resistance to proteolytic degradation by proteinase K relative to the linear peptide prototype. In silico studies indicated that the introduction of a hydrocarbon staple vs. a lactam bridge likely perturbs critical interactions required for proper binding of the peptide to the Li-TryR monomer.

Graphical abstract: Comparison of hydrocarbon-and lactam-bridged cyclic peptides as dimerization inhibitors of Leishmania infantum trypanothione reductase

Supplementary files

Article information

Article type
Paper
Submitted
16 Apr 2015
Accepted
17 Jun 2015
First published
19 Jun 2015

RSC Adv., 2015,5, 55784-55794

Comparison of hydrocarbon-and lactam-bridged cyclic peptides as dimerization inhibitors of Leishmania infantum trypanothione reductase

P. A. Sánchez-Murcia, M. Ruiz-Santaquiteria, M. A. Toro, H. de Lucio, M. Á. Jiménez, F. Gago, A. Jiménez-Ruiz, M. Camarasa and S. Velázquez, RSC Adv., 2015, 5, 55784 DOI: 10.1039/C5RA06853C

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements