Unusual activity pattern of leucine aminopeptidase inhibitors based on phosphorus containing derivatives of methionine and norleucine

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 26; no. 2; p. 155
• Main Authors: Pícha, Jan, Liboska, Radek, Buděšínský, Miloš, Jiráček, Jiři, Pawełczak, Małgorzata, Mucha, Artur
• Format: Journal Article
• Language: English
• Published: England 01-04-2011
• Subjects: Animals; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Kidney - enzymology; Leucyl Aminopeptidase - antagonists & inhibitors; Methionine - chemistry; Methionine - pharmacology; Molecular Structure; Norleucine - chemistry; Norleucine - pharmacology; Phosphorus - chemistry; Swine
• ISSN: 1475-6374
• DOI: 10.3109/14756366.2010.482047

Ligands containing bulky aliphatic P1 residues exhibit a high affinity towards cytosolic leucine aminopeptidase, a bizinc protease of biomedical significance. According to this specificity, a series of phosphonic and phosphinic compounds have been put forward as novel putative inhibitors of the enzyme. These phosphonic and phosphinic compounds were derivatives of methionine and norleucine as both single amino acids and dipeptides. The designed inhibitors were synthesised and tested towards the peptidase isolated from porcine kidneys using an improved separation procedure affording superior homogeneity. Unexpectedly, organophosphorus derivatives of methionine and norleucine exhibited moderate activity with K(i) values in the micromolar range.