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

Figures & data

Figure 1.  SDS-polyacrylamide gel electrophoresis after the enzyme purification (the molecular weights of the markers are indicated on the left). From the left: lane l: molecular weight markers, lane 2: the crude extract, lane 3: 40-65% ammonium sulphate precipitation, lane 4: Phenyl Sepharose fraction, lane 5: Macro-Prep High Q fraction. The gel was stained with Coomassie Brilliant R-250.

Figure 2.  Selection of α-aminophosphonic acid inhibitors of LAP: analogues of natural (L-Val-P [30] and L-Leu-P [29]) and non-natural (hPhe-P and hTyr-P [32]) amino acids, and their activity towards LAP.

Figure 3.  Newly designed and synthesised inhibitors of leucine aminopeptidase derivatives of methionine and norleucine.

Table 1.  The inhibitory activity of the phosphorus containing amino acid and dipeptide derivatives of methionine and norleucine towards the cytosolic leucine aminopeptidase.

Compound		Ki [μM]
1 (R,S)		22.6
2 (R,S)		22
3 (R,S)		58
4 (R,S)		73.9
5 (R,S) and (R,S)4 diastereoisomers		3.64*
6 (RS,SS)2 diastereoisomers		268.7
7 (RS,SS)2 diastereoisomers		219
8 (RS,SS)2 diastereoisomers		No inhibition up to 0.67 mM inhibitor concentration

* slow-binding, mechanism A

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