First example of peptides targeting the dimer interface of Leishmania infantum trypanothione reductase with potent in vitro antileishmanial activity
| Autor: | Federico Gago, Antonio Jiménez-Ruiz, Miguel A. Toro, Kilian Jesús Gutierrez, Héctor de Lucio, Filipa A.C. Carneiro, Sonia de Castro, Sonsoles Velázquez, Marta Ruiz-Santaquiteria, Pedro A. Sánchez-Murcia, María-José Camarasa |
|---|---|
| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Comunidad de Madrid |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Proteases Protein-protein interactions Stereochemistry Antiprotozoal Agents Molecular Dynamics Simulation 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Oxidoreductase Drug Discovery NADH NADPH Oxidoreductases Enzyme Inhibitors Leishmania infantum Cells Cultured Cell Proliferation Pharmacology chemistry.chemical_classification biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry Cell-penetrating peptides General Medicine biology.organism_classification Cyclic peptide 0104 chemical sciences Amino acid Helix stabilization PyBOP 030104 developmental biology Enzyme chemistry Biochemistry Lactam Trypanothione reductase Peptides Dimerization |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1768-3254 |
| Popis: | Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.ejmech.2017.04.020 A series of 9-mer and 13-mer amide-bridged cyclic peptides derived from the linear prototype Ac-PKIIQSVGIS-Nle-K-Nle-NH (Toro et al. ChemBioChem 2013) has been designed and synthesized by introduction of the lactam between amino acid side chains that are separated by one helical turn (i, i+4). All of these compounds were tested in vitro as both dimerization and enzyme inhibitors of Leishmania infantum trypanothione reductase (Li-TryR). Three of the 13-mer cyclic peptide derivatives (3, 4 and 6) inhibited the oxidoreductase activity of Li-TryR in the low micromolar range and they also disrupted enzyme dimerization. Cyclic analogues 3 and 4 were more resistant to proteases than was the linear prototype. Furthermore, the most potent TryR inhibitors in the linear and cyclic series displayed potent in vitro activity against Leishmania infantum upon conjugation with cationic cell-penetrating peptides. To date, these conjugated peptides can be considered the first example of TryR dimerization inhibitors that are active in cell culture. We thank the Spanish Government (MINECO/FEDER Projects SAF2012-39760-C02 and SAF2015-64629-C2) and Comunidad de Madrid (BIPEDD-2-CM ref. S-2010/BMD-2457) for financial support |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect