Aspartate protease inhibitors

These aspartic protease inhibitors are also "lead compounds" in the development of inhibitors of HIV protease. As in statine-based inhibitors, the site of occupancy by the catalytic H20 (green in Eq. 12-23) is occupied in the inhibitor by something that mimics a tetrahedral intermediate with - CHOH -P02H etc.bb Tremendous efforts are being expended in designing these inhibitors and considerable... 

A variety of aspartic protease inhibitor (API) proteins have been resolved from plants [122-135] of which the best characterized at the gene and protein level are those from Solanum tuberosum (potato) (Solanaceae) [124-134] (Table 4). The potato aspartic protease inhibitor proteins are typically about 190 residues (about 20 kDa), have 3 disulphide bridges, are homologous to the soybean trypsin inhibitor (Kunitz) family Pis [133] and can also inhibit trypsin [124-134] (Table 4). 

Table 4. Plant aspartic protease inhibitor proteins...

Angiotensin I converting enzyme Acquired immunodeficiency syndrome Aspartic protease inhibitor Bowman Birk protease inhibitor protein Chymotrypsin Cysteine protease inhibitor Endothelin-converting enzyme Elastase... 

Tossi A, Bonin I, Antcheva N, Norbedo S, Benedetti F, Miertus S, Nair AC, Maliar T, Dal Bello F, Palu G, Romeo D, Aspartic protease inhibitors—An integrated approach for the design and synthesis of diaminodiol-based peptidomimetics, Eur. J. Biochem., 267 1715-1722, 2000. 

This clearly resembles the inhibition mode of the serine and cysteine protease inhibitors described above. Iterative refinement (Figure 1.18), e.g., by variation of ring size and symmetrization of the functional decoration pattern, combined with subsequent extrapolation of the renin-specific finding to the entire aspartate protease family, is the apparent basis for a new generation of nonpeptide, lead-like inhibitors with multiple therapeutically relevant endpoint opportunities. The five-membered 3,4-di(aminomethyl)-pyrrolidine (Figure 1.18) served as the core structure for highly active aspartate protease inhibitors [101]. 

Approaches to Enzyme Inhibition Aspartic Proteases and Aspartic Protease Inhibitors Cysteine Proteases and Cysteine Protease Inhibitors Metalloproteinases, Biophysics and Chemistry of Serine Proteases and Serine Protease Inhibitors... 

Classical TSA inhibitors of cysteine and serine proteases differ from the metallo- and aspartic protease inhibitors in that they mimic the tet-... 

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. 

Figure 4.8. Hydrogen bonds between a prototypical aspartic protease inhibitor (acetylpepstatin) and HIV-l protease. The residues are labeled at the C-p position (C-a for glycine). The residues labeled 25-50 are from monomer A, those labeled 225-250 are from monomer B, and those labeled...

BACE-1 is a membrane-anchored aspartic acid protease that is localized to the acidic compartments of endosomes and lysosomes in the CNS and has an optimal enzymatic activity at around pH 5. As a consequence, a BACE-1 inhibitor needs to be able to cross the blood-brain barrier and to have a significant non-protein bound fraction in order to reach the active site of the enzyme. This makes traditional aspartic protease inhibitors, which typically are large and peptidic, unsuitable as BACE-1 inhibitors. Moreover, the BACE-1 active site is extended, shallow and hydrophilic (Fig. 2) [99]. Therefore, the development of potent, selective, orally active, and brain penetrant low MW compounds has been a big challenge for the pharmaceutical industry [101, 102],... 

Ripka, A.S., Satyshur, K.A., Bohacek, R.S. and Rich, D.H. (2001) Aspartic protease inhibitors designed from computer-generated templates bind as predicted. Org. Lett. 3 2309-2312. 

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