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Aspartic proteases are a widely known enzyme class that play an important role in the regulation of physiological processes such as blood pressure (Renin),digestion (Pepsin) and degradation of endocytosed proteins (Cathepsin D). They are also crucial for the progress of severe diseases caused either by parasites like malaria (Plasmepsin) and viruses like HIV (HIV protease) or neurodegenerative disorders including Alzheimer disease (b-Secretase). Since the catalytic mechanism of aspartic proteases was first postulated, several transition state analogues have been designed by replacing the dipeptidyl cleavage site of the specific peptide substrate. A key structural element in most transition state isosteres is a hydroxyl moiety that interacts with the two catalytically active aspartic acids via hydrogen bonds. This secondary hydroxyl group replaces a catalytic water molecule in the active site and mimics the tetrahedral intermediate that is usually formed upon amide bond hydrolysis of the native substrate. Here, we present a series of hydroxyethylenesulfones as novel transition state analogues. In this study the hydroxyethylenesulfones have been synthesized and evaluated for their ability to inhibit aspartic protease. The novel lead structure motif is derived from scaffolds of already known inhibitors targeting distinct aspartic proteases. One further rational design strategy for pyrrolidinedimethylenediamines was derived by adoption of key structural elements from classical peptidomimetics linked with a non-peptide heterocyclic core structure. It is illustrated the structural requirements for our novel prototype inhibitor in a schematic manner starting from crystal structures of HIV protease and Cathepsin D with the classical peptidomimetic pepstatin. The incorporated hydroxyl group in the statine core interacts via hydrogen bonds with the catalytic aspartic acids. Further important hydrogen bonds can be recognized by two indicated carbonyl groups which either interact with the flap water in the active site of HIV protease or the nitrogens of Gly 79 and Asp 80 of the Cathepsin D backbone.In order to evaluate whether the pyrrolidinediemethylenediamines are a valid new lead structure the central pyrrolidine core was decorated with already optimized site chains derived from the HIV protease inhibitor Amprenavir and the Cathepsin D inhibitor.