期刊
BIOPOLYMERS
卷 106, 期 3, 页码 330-344出版社
WILEY
DOI: 10.1002/bip.22844
关键词
allozyme; enzyme inhibition; glutathione analogue; glutathione transferase; isoenzyme; molecular modeling; multidrug resistance
资金
- action THALES: Glutathione transferases, multifunctional molecular tools in red and green biotechnology falling under the Operational Program Education and Lifelong Learning
- European Social Fund
- National Resources
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. (C) 2016 Wiley Periodicals, Inc.
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