APOMORPHINE INHIBITORS OF AMYLOID-Beta (ABeta) FIBRIL FORMATION AND THEIR USE IN AMYLOIDOSIS BASED DISEASE

摘要

Described is a new class of small molecule inhibitors of amyloid β protein (Aβ) aggregation, based on apomorphine. These molecules target the nucleation phase of Aβ self-assembly and interfere effectively with aggregation of Aβ 1-40 into amyloid fibrils invitro as determined by transmission electron microscopy, Thioflavin T (ThT) fluorescence, and velocity sedimentation. Structure-activity studies using apomorphine analogues demonstrate that 10, 11-dihydroxy substitutions of the D ring are preferred for the inhibitory effectiveness of these aporphines, and that methylation of these hydroxyl groups reduces their inhibitory potency. The ability of these small molecules to inhibit Aβ amyloid fibril formation appears to be linked to their ability to undergo auto-oxidation in solution, implicating an auto-oxidation product as the active A&beta, inhibitor. Sedimentation velocity and electron microscopy studies demonstrate that apomorphine and analogues facilitate oligomerization of Aβ into short nonfibrillar soluble assemblies, but inhibit Aβ fibrilization.