Aspartic peptidase inhibitors

Dash C, Kulkarni A, Dunn B, Rao M. 2003. Aspartic peptidase inhibitors implications in drug development. Grit Rev Biochem Mol Biol 38 89-119. 

This method is compatible with many functional groups and shows considerable selectivity. Phosphonic acid esters may be cleaved in the presence of carboxylic acid esters, and phosphonate methyl esters are cleaved approximately 25 times faster than the isopropyl esters. For example, the phosphonate methyl ester of the hexapeptide analogue 78 was cleaved with TMSBr to give the aspartic peptidase inhibitor 79 in 64% yield (Scheme 28). 66 ... 

Inhibitors which interact only with peptidases of one catalytic type include pepstatin (aspartic peptidases) E64 (cysteine peptidases from clan CA) diisopropyl fluorophosphates (DFP) and phenylmethane sulfonyl-fluoride (PMSF) (serine peptidases). Bestatin is a useful inhibitor of aminopeptidases. 

The peptidase inhibitors, (82) and (83), are actually amino acid and transition-state mimics pieced together to emulate the typical ligand-bound extended p-strand inhibitor conformation. The structurally distinct heterocyclic aspartic protease inhibitors (85-86) and (87-88) are non-peptide peptidomimetics because of their remote structural relationship to native peptide substrates. Yet these two distinct peptidomimeticclasses bind to the same active site topography. These structurally distinct peptidomimetics selectively stabilize closely related enzyme conformations. 

Novel PS-related famihes of proteins (IMPAS/PSH/signal peptide peptidases [SPSs]) have been identified (163). Intramembrane protease-associated or intramembrane protease aspartic protein Impas 1 (1MP1)/SPS induces intramembranous cleavage of PSl holoprotein in cultured cells coexpressing these proteins. Mutations in evolutionary invariant sites in hlMPl or specific y-secretase inhibitors abolish the hlMPl-mediated endoproteolysis of PSl. In contrast, AD-like mutations in neither hlMPl nor PSl substrate abridge the PSl cleavage (163). 

Weihofen, A., Lemberg, M.K., Friedmann, E., et al. (2003) Targeting presenilin-type aspartic protease signal peptide peptidase with y-secretase inhibitors. J. Biol. Chem., 278, 16528-16533. 

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