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Issue 69, 2015
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Comparison of hydrocarbon-and lactam-bridged cyclic peptides as dimerization inhibitors of Leishmania infantum trypanothione reductase

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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

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Supplementary files

Article information


Submitted
16 Apr 2015
Accepted
17 Jun 2015
First published
19 Jun 2015

RSC Adv., 2015,5, 55784-55794
Article type
Paper

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

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