Plasmepsin inhibition

Libraries of hundreds to thousands of spatially separate inhibitors have been prepared and screened to identify small molecule inhibitors of the human protease cathepsin D and the essential malarial proteases, plasmepsins I and II. The best inhibitors do not incorporate any amino adds and possess high affinity (Kj<5 nM).1241 Furthermore, these lead compounds were optimized by combinatorial methods for good physicochemical properties and minimal binding to human serum albumin. The optimized inhibitors effectively block cathepsin D-mediated proteolysis in human hippocampyl slices and are currently being used to evaluate the therapeutic potential of cathepsin D inhibition in the treatment of Alzheimer s disease. Additionally, the plasmepsin inhibitors serve as promising leads for the treatment of malaria. 

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