Synthesis and glutathione S-transferase structure-affinity relationships of nonpeptide and peptidase-stable glutathione analogues.
A series of nonpeptidic glutathione analogues where the peptide bonds were replaced by simple carbon-carbon bonds or isosteric E double bonds were prepared. The optimal length for the two alkyl chains on either side of the mercaptomethyl group was evaluated using structure-affinity relationships. Affinities of the analogues 14a-f, 23, and 25 were evaluated for a recombinant GST enzyme using a new affinity chromatography method previously developed in our laboratory. Analysis of these analogues gives an additional understanding for GST affinity requirements: (a) the carbon skeleton must conserve that of glutathione since analogue 14a showed the best affinity (IC50 = 5.2 microM); (b) the GST G site is not able to accommodate a chain length elongation of one methylene group (no affinity for analogues 14c,f); (c) a one-methylene group chain length reduction is tolerated, much more for the "Glu side" (14d, IC50 = 10.1 microM) than for the "Gly side" (14b, IC50 = 1800 microM); (d) the mercaptomethyl group must remain at position 5 as shown from the null affinity of the 6-mercaptomethyl analogue 14e; (e) the additional peptide isosteric E double bond (25) or hydroxyl derivative (23) in 14e did not help to retrieve affinity. This work reveals useful information for the design of new selective nonpeptidic and peptidase-stable glutathione analogues.
Klotz
P
P
Laboratoire de Chimie Organique, Université Sidi Mohamed Ben Abdellah, Faculté des Sciences Dhar Mahrez BP1796, Atlas Fès, Maroc.
Slaoui-Hasnaoui
A
A
Banères
J L
JL
Duckert
J F
JF
Rossi
J C
JC
Kerbal
A
A
D000818:Animals; D002846:Chromatography, Affinity; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism*; D005978:Glutathione / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000378:metabolism*; D018716:Molecular Mimicry; D011485:Protein Binding; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D012549:Schistosoma japonicum / Q000201:enzymology; D013329:Structure-Activity Relationship
D011994:Recombinant Proteins; D005982:Glutathione Transferase; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D005978:Glutathione