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Design and Synthesis of Statine-Based Cell-Permeable Peptidomimetic Inhibitors of Human β-Secretase

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journal contribution
posted on 11.04.2003, 00:00 by Roy K. Hom, Larry Y. Fang, Shumeye Mamo, Jay S. Tung, Ashley C. Guinn, Don E. Walker, David L. Davis, Andrea F. Gailunas, Eugene D. Thorsett, Sukanto Sinha, Jeroen E. Knops, Nancy E. Jewett, John P. Anderson, Varghese John
We describe the development of statine-based peptidomimetic inhibitors of human β-secretase (BACE). The conversion of the peptide inhibitor 1 into cell-permeable peptidomimetic inhibitors of BACE was achieved through an iterative strategy of conceptually subdividing 1 into three regions:  an N-terminal portion, a central statine-containing core, and a C-terminus. Replacement of the amino acid residues of 1 with moieties with less peptidic character was done with retention of BACE enzyme inhibitory activity. This approach led to the identification of the cell-permeable BACE inhibitor 38 that demonstrated BACE-mechanism-selective inhibition of Aβ secretion in human embryonic kidney cells.