title: Elongation factor 2 as a target for selective inhibition of protein synthesis in vitro by the novel aromatic bisamidine.
abstract: The effect of the novel aromatic bisamidine 1 on protein synthesis in cell-free translational system isolated from rat livers was studied. The bisamidine 1 caused inhibition of [14C]leucine incorporation into proteins proportionally to its concentration. To establish a precise mechanism of inhibition, we evaluated the effect of the bisamidine 1 on the isolated ribosomes and purified to homogeneity elongation factors. Preincubation of the bisamidine 1 with ribosomes resulted in partial inhibition of their activity in whole elongation system. The eucaryotic elongation factor 1 (eEF-1) was not significantly affected by the bisamidine 1. In contrast to eEF-1, the bisamidine 1 preincubated with the eucaryotic elongation factor 2 (eEF-2) caused total inhibition of its activity in the translocation process. The inhibitory effect of the bisamidine 1 on eEF-2 activity was confirmed in diphtheria toxin-dependent ADP-ribosylation reaction. The results suggest a high action specificity of the bisamidine 1 as potential anticancer drug, since the primary target seems to be highly conserved protein-elongation factor 2.
authors.affiliation: Department of Medical Chemistry, Medical Academy of Bialystok, Poland. angajko@amb.ac.bialystok.pl
authors.forename: Anna
authors.initials: A
authors.lastname: Gajko-Galicka
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Bielawski
authors.forename: Krystyna
authors.initials: K
authors.lastname: Sredzinska
authors.forename: Anna
authors.initials: A
authors.lastname: Bielawska
authors.forename: Andrzej
authors.initials: A
authors.lastname: Gindzienski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002474:Cell-Free System; D005663:Furans / Q000494:pharmacology*; D066298:In Vitro Techniques; D007930:Leucine / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D020652:Peptide Elongation Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D051381:Rats; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D020652:Peptide Elongation Factor 2; D011500:Protein Synthesis Inhibitors; C469777:bisamidine; D007930:Leucine