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

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dc.citation.issueNumberFEBen_US
dc.citation.volumeNumber9en_US
dc.contributor.authorAkhmadishina, R. A.en_US
dc.contributor.authorGarifullin, R.en_US
dc.contributor.authorPetrova, N. V.en_US
dc.contributor.authorKamalov, M. I.en_US
dc.contributor.authorAbdullin, T. I.en_US
dc.date.accessioned2019-02-21T16:08:48Z
dc.date.available2019-02-21T16:08:48Z
dc.date.issued2018en_US
dc.departmentInstitute of Materials Science and Nanotechnology (UNAM)en_US
dc.departmentNanotechnology Research Center (NANOTAM)en_US
dc.description.abstractAlthough 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) units. The TPP moiety noticeably promoted YRFK cleavage by trypsin, but effectively prevented digestion of more resistant YrFK attributed, respectively, to structure-organizing and shielding effects of the TPP cation on conformational variants of the tetrapeptide motif. The TPP moiety enhanced radical scavenging activity of the modified YRFK in a model Fenton-like reaction, whereas decreased reactivity was revealed for both YrFK and its TPP derivative. 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. 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 type of oxidative factor, order of treatment and peptide structure. Pronounced cell-protective effect was established for the TPP-modified oligopeptides, which surpassed that of the unmodified motifs. The protease-resistant TPP-modified 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.
dc.identifier.doi10.3389/fphar.2018.00115
dc.identifier.issn1663-9812
dc.identifier.urihttp://hdl.handle.net/11693/50432
dc.language.isoEnglish
dc.publisherFrontiers Media S.A.
dc.relation.isversionofhttps://doi.org/10.3389/fphar.2018.00115
dc.rightsinfo:eu-repo/semantics/openAccess
dc.source.titleFrontiers in Pharmacologyen_US
dc.subjectAntioxidant activityen_US
dc.subjectAromatic-cationic oligopeptidesen_US
dc.subjectCytoprotectionen_US
dc.subjectFenton reactionen_US
dc.subjectNeuronal cellsen_US
dc.subjectOxidative damageen_US
dc.subjectProtease stabilityen_US
dc.subjectTriphenylphosphonium compoundsen_US
dc.titleTriphenylphosphonium moiety modulates proteolytic stability and potentiates neuroprotective activity of antioxidant tetrapeptides in vitroen_US
dc.typeArticleen_US
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Institute of Materials Science and Nanotechnology (UNAM)
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