Novel nonpeptidic inhibitors of peptide deformylase.
A novel series of nonpeptidic compounds structurally related to the known anticholesteremic thyropropic acid were found to inhibit Escherichia coli peptide deformylase (PDF), with IC50 values in the low-micromolar range. Kinetic analysis of [4-(4-hydroxyphenoxy)-3,5-diiodophenyl]acetic acid reveals competitive inhibition, with a Ki value of 0.66 +/- 0.007 microM. A structure-activity relationship study demonstrates that the carboxylate is required for activity, while the distal phenolic function can be methylated without significant effect. Either decreasing the number of iodine atoms on the molecule to one or increasing the number of iodine atoms to four results in the loss of an order of magnitude in potency. These compounds are the first nonpeptidic inhibitors disclosed and represent a template from which better inhibitors might be designed.
Jayasekera
M M
MM
Department of Biochemistry, Pfizer Global Research and Development, Ann Arbor, Michigan 48105, USA.
Kendall
A
A
Shammas
R
R
Dermyer
M
M
Tomala
M
M
Shapiro
M A
MA
Holler
T P
TP
D000581:Amidohydrolases; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D000924:Anticholesteremic Agents / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D005798:Genes, Bacterial; D007700:Kinetics; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000924:Anticholesteremic Agents; D017931:DNA Primers; D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D000626:Aminopeptidases; D000581:Amidohydrolases; C084507:peptide deformylase