Hom Roy K, Fang Larry Y, Mamo Shumeye, Tung Jay S, Guinn Ashley C, Walker Don E, Davis David L, Gailunas Andrea F, Thorsett Eugene D, Sinha Sukanto, Knops Jeroen E, Jewett Nancy E, Anderson John P, John Varghese
Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, California 94080, USA.
J Med Chem. 2003 May 8;46(10):1799-802. doi: 10.1021/jm025619l.
We describe the development of statine-based peptidomimetic inhibitors of human beta-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 Abeta secretion in human embryonic kidney cells.
我们描述了基于他汀的人β-分泌酶（BACE）拟肽抑制剂的开发。通过将肽抑制剂1概念性地细分为三个区域的迭代策略，实现了将肽抑制剂1转化为细胞可渗透的BACE拟肽抑制剂：N端部分、含他汀的中央核心和C端。用具有较少肽性质的部分取代1的氨基酸残基，同时保留BACE酶抑制活性。这种方法导致鉴定出细胞可渗透的BACE抑制剂38，其在人胚肾细胞中表现出对β淀粉样蛋白分泌的BACE机制选择性抑制。
