Metallo-aminopeptidase inhibitors

Abstract

Aminopeptidases are enzymes that selectively hydrolyze an amino acid residue from the N-terminus of proteins and peptides. They are important for the proper functioning of prokaryotic and eukaryotic cells, but very often are central players in the devastating human diseases like cancer, malaria and diabetes. The largest aminopeptidase group include enzymes containing metal ion(s) in their active centers, which often determines the type of inhibitors that are the most suitable for them. Effective ligands mostly bind in a non-covalent mode by forming complexes with the metal ion(s). Here, we present several approaches for the design of inhibitors for metallo-aminopeptidases. The optimized structures should be considered as potential leads in the drug discovery process against endogenous and infectious diseases.

Fig. 1

Catalytic roles considered for the metal (zinc) ions in the mechanism of metallo-aminopeptidases action: stabilization of a highly reactive hydroxide ion (mechanism A), complexation of the oxygen atom of the scissile peptide bond to facilitate the nucleophilic attack of a water molecule (mechanism B).

Fig. 2

Alternatives of catalytic mechanisms considered for metallo-aminopeptidases: glutamate acting as a nucleophile – formation of a covalent enzyme–inhibitor complex and its fast hydrolysis (mechanism C), bridging of a hydroxide ion in binuclear metal centers (mechanism D).

Fig. 3

The general structure of α-aminoalkanephosphonic acids (1) and phosphinic pseudodipeptides (2) applied for inhibition of neutral aminopeptidases.

Fig. 4

Selected phosphonic amino acids analogues and their inhibition of the mammalian leucine and alanine aminopeptidases.

Fig. 5

Phosphorus containing pseudodipeptides as inhibitors of the M17 leucine aminopeptidase.

Fig. 6

Phosphinic pseudotripeptides as highly effective inhibitors of the alanyl and glutamyl metallo-aminopeptidases.

Fig. 7

The general structures of phosphonic compounds α-functionalized with an additional heteroatom group to enhance the coordination of the catalytic zinc ion in the active site of the aminopeptidase.

Fig. 8

The structure of bestatin and its inhibition of selected mammalian aminopeptidases.

Fig. 9

Structure of bestatin derivatives and their inhibition of selected aminopeptidases.

Fig. 10

Structure of Activity Based Probe based on structure of bestatin for labeling of aminopeptidases.

Fig. 11

The structures of phebestin, probestin and amastatin and their activity towards aminopeptidase N.

Fig. 12

Amino acid derived hydroxamate inhibitors of neutral aminopeptidases.

Fig. 13

A selection of hydroxamic acid inhibitors of aminopeptidase N and methionine aminopeptidases (recombinant human, h, and Escherichia coli, Ec).

Fig. 14

An example of an amide-hydroxamic acid inhibitor of aminopeptidase N with the antiparasitic activity.

Fig. 15

The chemical structure of Tosedostat, a hydroxamate prodrug of the acid inhibitor of intracellular aminopeptidases.

Fig. 16

Potent 2-aminothiol inhibitors of the aminopeptidases B and N, the analogues of the natural amino acids.

Fig. 17

Optimization of the lead Glu-thiol structure (40) to achieve selective inhibition of aminopeptidase N versus glutamyl aminopeptidase (compounds 40, 41 and 43 were tested as the S enantiomers, whereas compound 42 as the racemic mixture).

Fig. 18

The structures of MetAP2 covalent inhibitors – fumagillin, ovalicin and TNP-470.

Fig. 19

Selected potent inhibitors of the human MetAP2 based on the 1,2,3 and 1,2,4-triazole scaffolds. Compounds 53 inhibited the bacterial MetAP1 and allowed the elucidation of the triazoles binding mode to the enzyme catalytic site.

Fig. 20

Inhibition of the cobalt dependent Escherichia coli methionine aminopeptidase type 1 by thiazole based compounds.

Fig. 21

Inhibition of the cobalt dependent Escherichia coli MetAP1 by selected thiabendazoles 60–62. 2-(2-Pipyridinyl)pyrimidine inhibitor (63) of human and Plasmodium falciparum methionine aminopeptidases.

Fig. 22

The structure of 1-butaneboronic acid.

Fig. 23

Structures and activity of α-aminoboronic acids.

Fig. 24

Structures of α-aminoaldehydes.

Fig. 25

Structure and activity of 3-amino-2-hydroxy-propionaldehyde and 3-amino-1-hydroxypropan-2-one phenylalanine derivatives.

Fig. 26

Optimization of the anthranilic sulfonamides structure as inhibitors of MetAP2 and potential anti-cancer agents.

Fig. 27

A quinolinyl sulfonamide as inhibitor of EcMetAP1.

Fig. 28

3-Amino-2-tetralone derivatives and their activity towards APN.

Fig. 29

3-Amino-2-tetralone derivatives and activity towards APN, LAP and LTA₄H.

Fig. 30

Structures of gallic derivatives with 4-amino-l-proline scaffold as inhibitors of aminopeptidase N.

Fig. 31

Structures of gallic derivatives with l-iso-glutamine and cyclo-l-iso-glutamine scaffold as inhibitors of aminopeptidase N.

Fig. 32

Structure of betulinic acid.

Fig. 33

Structure of curcumin and its activity towards APN.