Probing pockets S2-S4' of the gamma-secretase active site with (hydroxyethyl)urea peptidomimetics.
(Hydroxyethyl)urea peptidomimetics are potent inhibitors of gamma-secretase that are accessible in a few synthetic steps. Systematic alteration of P2-P4' revealed that the corresponding S2-S4' active site pockets accommodate a variety of substituents, consistent with the fact that this protease cleaves a variety of single-pass membrane proteins; however, phenylalanine is not well tolerated at P2'. A compound spanning P2-P3' was identified as a low nM inhibitor of gamma-secretase activity both in cells and under cell-free conditions.
Esler
William P
WP
Center for Neurologic Diseases, Harvard Medical School and Brigham and Womens Hospital, Boston, MA 02115, USA.
Das
Chittaranjan
C
Wolfe
Michael S
MS
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D010450:Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D015394:Molecular Structure; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D010446:Peptide Fragments; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D006918:Hydroxyurea