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[摘要]：Recently, we reported substrate-based pentapeptidic beta-secretase (BACE1) inhibitors with a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent BACE1 inhibitory activity in enzyme and cell assays, with KMI-429 showing in vivo inhibition of A beta production. We also designed and synthesized nonpeptidic and small-sized BACE1 inhibitors using "in-silico conformational structure-based design". By studying the structure-activity relationship of these inhibitors, we found that the sigma-pi interaction of an inhibitor with the BACE1-Arg235 side chain played a key role in the inhibition of BACE1. We speculated that a peptide capable of binding to the BACE1-Arg235 side chain via the sigma-pi interaction might exhibit BACE1 inhibitory activity. Hence, we designed and synthesized a series of peptides that were modified at the P-2 position and found that some of these peptides exhibited a potent BACE1 inhibitory activity despite their structural similarity to the BACE1 substrate. |
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