Design of Substrate-Based Inhibitors of Human β-Secretase
journal contribution
posted on 2001-12-20, 00:00 authored by Jay S. Tung, David L. Davis, John P. Anderson, Don E. Walker, Shumeye Mamo, Nancy Jewett, Roy K. Hom, Sukanto Sinha, Eugene D. Thorsett, Varghese JohnBy use of the effectively cleaved <i>β</i>-secretase (BACE)
substrate (<b>1</b>), incorporation of a statine in P<sub>1</sub> resulted in a weak
inhibitor <b>13 </b>of the enzyme. Further substitution of P<sub>1</sub>‘-Asp by
P<sub>1</sub>‘-Val in <b>13</b> results in a potent inhibitor <b>22</b> of BACE. Removal
of the P<sub>10</sub>−P<sub>5</sub> residues on the N-terminal part of inhibitor <b>22</b>
resulted in no loss of potency (<b>23</b>). C-terminal truncations of
inhibitor <b>22</b> generally led to significant loss of potency.
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