Aspartic proteases non-protein inhibitors

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],... 

All the HIV protease inhibitors have in common a specific effect against the aspartic HIV protease that cleaves viral proteins to yield structural proteins. Competitive inhibition of this process by the protease inhibitors results in the production of immature, non-infections virus particles. These drugs are also characterized by their high specificity, being more than a thousand-fold more active against viral than human aspartic proteases. 

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