The challenging task of converting the relatively large and linear peptidic inhibitors of BACE-1, reported so far in the literature, into proteolitically more stable peptidomimetic structures such as peptoids, hybrid peptide-peptoids and retroinverso analogs failed due to the loss of inhibitory potency. Conversely, molecular modeling experiments based on the known X-ray structures of BACE 1/peptidic inhibitors led to the design of novel cyclic peptidic structures of reduced size and containing statine as the transition-state analogue. These were found to retain efficient affinities for the aspartic protease and thus to present the statine moiety in correct orientation to the active site of the enzyme with the short peptide-backbone in the β-type extended conformation for additional interactions with the active-site cleft. First attempts to improve the structure of the transition-state analogue statine and to restrict the side-chain cyclized peptide backbone in the extended conformation by incorporation of aminobenzoic acid residues, led to important hints for further developments of peptidomimetic cyclic compounds as BACE-1 inhibitors with enhanced stability against protease degradation and thus more suitable for in vivo biological studies on the role of this enzyme in amyloidogenesis in Alzheimer´s disease. The difficult problem of developing MMP inhibitors capable of differentiating the gelatinases MMP-2 and -9 from the other members of the large MMPs family including the collagenases, was again tackled by a structure-based design relying on the peculiar interaction of a propeptide portion in MMP-9 with a well delineated hydrophobic pocket of the third fibronectin domain. By exploiting the binding affinities of metal chelating groups at the active site and the exosite binding of a polipeptide portion to the fibronectin domain, application of the concept of bivalent inhibitors was attempted. For this purpose molecular modeling experiments were performed to assess the size of the PEG spacer chosen as linker of the two binding groups. Correspondingly PEG spacers of different lengths were used to crosslink a hydroxamate head group containing phenylalanine as P1´ residue for recognition and binding to the MMP-9 active site, and a pentapeptide head for exosite binding. First enzymatic assays seem to confirm the working hypothesis. In summary, progresses were achieved in both projects that are most promising for further developments of low mass peptidomimetic inhibitors of BACE-1 and of highly selective inhibitors of the two gelatinases by applying the concept of bivalency.
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The challenging task of converting the relatively large and linear peptidic inhibitors of BACE-1, reported so far in the literature, into proteolitically more stable peptidomimetic structures such as peptoids, hybrid peptide-peptoids and retroinverso analogs failed due to the loss of inhibitory potency. Conversely, molecular modeling experiments based on the known X-ray structures of BACE 1/peptidic inhibitors led to the design of novel cyclic peptidic structures of reduced size and containing s...
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