title: Glutathione analogues as substrates or inhibitors that discriminate between allozymes of the MDR-involved human glutathione transferase P1-1.
abstract: Glutathione (GSH) structure-guided tripeptide analogues were designed and synthesized by solid phase technology, purified (≥95%) by RP and/or GF column chromatography, to identify those that, compared with GSH, exhibited similar or higher binding and catalytic efficiency toward the MDR-involved human GSTP1-1 isoenzyme, and could discriminate between the allozymic expression products of the polymorphic human GSTP1 gene locus, designated as hGSTP1*A (Ile(104) /Ala(113) ), hGSTP1*B (Val(104) /Ala(113) ), and hGSTP1*C (Val(104) /Val(113) ). The analogues bear single amino acid alterations as well as alterations in more than one position. Some analogues showed remarkable allozyme selectivity, binding catalytically to A (I, II, IV, XII), to C (V and XVI), to A and C (III, VII, XIV) or to all three allozymes (XV). A heterocyclic substituent at positions 1 or 2 of GSH favors inhibition of A, whereas a small hydrophobic/hydrophilic amide substituent at position 2 (Cys) favors inhibition of B and C. Heterocyclic substituents at position 1, only, produce catalytic analogues for A, whereas less bulky and more flexible hydrophobic/hydrophilic substituents, at positions 1 or 3, lead to effective substrates with C. When such substituents were introduced simultaneously at positions 1 and 3, the analogues produced have no catalytic potential but showed appreciable inhibitory effects, instead, with all allozymes. It is anticipated that when GSH analogues with selective inhibitory or catalytic binding, were conjugated to allozyme-selective inhibitors of hGSTP1-1, the derived leads would be useful for the designing of novel chimeric inhibitors against the MDR-involved hGSTP1-1 allozymes. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 330-344, 2016.
authors.affiliation: Laboratory Οf Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, University of Patras, Rio, Greece.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Zompra
authors.affiliation: Laboratory of Enzyme Technology, Department of Biotechnology, Agricultural University of Athens, Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Georgakis
authors.affiliation: Laboratory Οf Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, University of Patras, Rio, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Pappa
authors.affiliation: Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens, Greece.
authors.forename: Trias
authors.initials: T
authors.lastname: Thireou
authors.affiliation: Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens, Greece.
authors.forename: Elias
authors.initials: E
authors.lastname: Eliopoulos
authors.affiliation: Laboratory of Enzyme Technology, Department of Biotechnology, Agricultural University of Athens, Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Labrou
authors.affiliation: Laboratory Οf Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, University of Patras, Rio, Greece.
authors.forename: Paul
authors.initials: P
authors.lastname: Cordopatis
authors.affiliation: Laboratory of Enzyme Technology, Department of Biotechnology, Agricultural University of Athens, Athens, Greece.
authors.forename: Yannis
authors.initials: Y
authors.lastname: Clonis
mesh_terms: D000494:Allosteric Regulation; D019943:Amino Acid Substitution; D001665:Binding Sites; D018432:Drug Resistance, Multiple / Q000235:genetics; D015870:Gene Expression; D056426:Genetic Loci; D005978:Glutathione / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D060327:Solid-Phase Synthesis Techniques / Q000379:methods; D013329:Structure-Activity Relationship
chemical_list: D007527:Isoenzymes; D009842:Oligopeptides; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005978:Glutathione
keywords: allozyme; enzyme inhibition; glutathione analogue; glutathione transferase; isoenzyme; molecular modeling; multidrug resistance