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Front. Pharmacol. | doi: 10.3389/fphar.2018.00115

Triphenylphosphonium moiety modulates proteolytic stability and potentiates neuroprotective activity of antioxidant tetrapeptides in vitro

Rezeda Akhmadishina1,  Ruslan Garifullin1, Natalia Petrova1, Marat Kamalov1 and  Timur I. Abdullin1*
  • 1Kazan Federal University, Russia

Although delocalized lipophilic cations have been identified as effective cellular and mitochondrial carriers for a range of natural and synthetic drug molecules, little is known about their effects on pharmacological properties of peptides. The effect of triphenylphosphonium (TPP) cation on bioactivity of antioxidant tetrapeptides based on the model opioid YRFK motif was studied. Two tetrapeptide variants with L-arginine (YRFK) and D-arginine (YrFK) were synthesized and coupled with carboxyethyl-TPP (TPP-3) and carboxypentyl-TPP (TPP-6) groups. The TPP moiety noticeably promoted YRFK endopeptidase cleavage by trypsin, but effectively prevented digestion of more resistant YrFK attributed, respectively, to structure-organizing and shielding effects of the TPP cation on stereochemical variants of the tetrapeptide motif. The TPP moiety enhanced radical scavenging activity of the modified YRFK in a model Fenton-like reaction, whereas low reactivity was revealed for YrFK and its TPP derivative. Both the starting motifs and modified oligopeptides, especially the TPP-6 derivatives, suppressed acute oxidative stress in neuronal PC-12 cells during a brief exposure similarly with glutathione (GSH). The effect of oligopeptides was compared upon culturing of PC-12 cells with CoCl2, L-glutamic acid, or menadione to mimic physiologically relevant oxidative states. The cytoprotective activity of oligopeptides significantly depended on the oxidative factor, order of treatment and peptide structure. Pronounced cell-protective effect was established for the TPP-modified oligopeptides, which surpassed that of GSH and the unmodified motifs. The protease-resistant TPP-derivative of YrFK showed the highest activity when administered 24 h prior to the cell damage. Our results suggest that the TPP cation can be used as a modifier for small therapeutic peptides to improve their pharmacokinetic and pharmacological properties.

Keywords: aromatic-cationic oligopeptides, triphenylphosphonium compounds, antioxidant activity, Fenton reaction, Neuronal Cells, Oxidative damage, Cytoprotection, Protease stability

Received: 06 Nov 2017; Accepted: 31 Jan 2018.

Edited by:

Victor Erokhin, Istituto Materiali per Elettronica e Magnetismo IMEM-CNR, Italy

Reviewed by:

Medardo Hernández, Complutense University of Madrid, Spain
Andrey Y. Abramov, UCL Institute of Neurology, United Kingdom  

Copyright: © 2018 Akhmadishina, Garifullin, Petrova, Kamalov and Abdullin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Timur I. Abdullin, Kazan Federal University, Kazan, Russia, tabdulli@gmail.com