Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Ruiz-Santaquiteria, M; de Castro, S; Toro, MA; de Lucio, H; Gutiérrez, KJ; Sánchez-Murcia, PA; Jiménez, MÁ; Gago, F; Jiménez-Ruiz, A; Camarasa, MJ; Velázquez, S.
Trypanothione reductase inhibition and anti-leishmanial activity of all-hydrocarbon stapled α-helical peptides with improved proteolytic stability.
Eur J Med Chem. 2018; 149(16):238-247
Doi: 10.1016/j.ejmech.2018.02.071
Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Sánchez Murcia Pedro Alejandro
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- Abstract:
- Trypanothione 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. Copyright © 2018 Elsevier Masson SAS. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- Antiprotozoal Agents - chemistry
- Drug Stability -
- Hydrocarbons - chemistry
- Leishmania infantum - drug effects
- NADH, NADPH Oxidoreductases - antagonists & inhibitors
- Peptides - chemistry
- Peptides - pharmacology
- Protein Conformation, alpha-Helical -
- Proteolysis -
- Protozoan Proteins - antagonists & inhibitors
- Find related publications in this database (Keywords)
- Stapled peptides
- Protein-protein interactions
- Trypanothione reductase
- Leishmania infantum
- Cell-penetrating peptides