Caspase-1 inhibitors design

Most caspase-inhibitor design strategies target their active sites and are based on caspase substrate preferences. Tetrapep-tide inhibitors, which are based on identihed sequences of the four amino acid recognition motifs, were shown to inhibit caspase family members selectively (24) (Fig. 2a). Overall, a typical peptide-based caspase inhibitor consists of three major structural components ... 

Small-molecule inhibitors of caspases would have obvious use as therapeutics. The current medicinal chemistry research literature is rich in studies attempting to achieve this important design goal. In early work, both reversible and irreversible peptide-based inhibitors of various caspases have been developed. Peptidomimetic ketones were also devised for example, acyloxymethyl ketones were designed and developed as potent, time-dependent irreversible caspase inhibitors. 

Fig. 8.3. (Bottom) Thiomethylketone D of (88) is used as an example of a caspase 3 inhibitor designed via a docking-based library generation protocol. S1 and S2 denote the interaction sites within the binding pocket of caspase 3. (Top right) The thiomethylketone scaffold that is used as the starting point for library design. (Top left) The eight R-groups used to attach to the R attachment point of the scaffold.

Protease substrate libraries can provide useful information about the enzyme sub-site preferences which can be applied to inhibitor design [268, 387-392]. Researchers at Merck have applied positonal-scanning combinatorial substrate libraries to identify an optimal substrate (Ac-WEHD-ACM) for caspase-1 which is a cysteine protease implicated in inflammation and apoptosis [390, 391], This information was then used to generate the po-... 

Tethering with extenders was also used to identify inhibitors to the antiinflammatory target caspase-1 [28, 29]. In this case, one of the same extenders previously designed for caspase-3 selected an entirely different set of fragments. This is consistent with different substrate peptide sequence preferences WEHD for caspase-1 vs DEVD for caspase-3 [30]. 

O Brien, T Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design. J. Med. 

In mammalian cells, there are multiple forms of enzymes within the same family, e.g., protein kinase C, phospholipase C, and caspase. A selective assay system would be instrumental in such cases to advance understanding of the respective role for each form within the same enzyme family. An example for design of a selective assay system for the superfamily of phospholipase A2 is provided in this chapter. Such a selective assay system may play a signihcant enabling role for PLA2 and other enzyme families in the discovery of inhibitors relevant to the treatment of pathologies involving those enzymes. 

Members of the lAP family inhibit caspases 3, 7 and 9 and interact with inhibitory Smac/DIABLO protein that is released from the mitochondria during apoptosis. They are over-expressed in some cancers. Peptide inhibitors of lAPs were then designed based on the Smac/DIABLO protein. The N-terminal sequence (AVPI) of Smac/DIABLO reacts with BIR3 of X-linked lAP (XIAP) and its N-terminal heptapetide promote procaspase-3 activation [241]. The... 

Sun H, Nikolovska-Coleska Z, Yang CY et al. Structure-based design, synthesis, and evaluation of conformationally constrained mimetics of the second mitochondria-derived activator of caspase that target the X-linked inhibitor of apoptosis protein/ caspase-9 interaction site. J Med Chem 2004 47 4147-4150. 

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