06 Aug 2002

Lead discovery is hampered by the absence of good cell-based assays in which to screen libraries against AβPP secretases and other targets. One participant presented a new strategy for using fluorescent proteins in cell-based assays for drug screening. Application of this strategy to in vivo studies would require acceptable endpoints, as well as the refinement of fluorophores active in the long-red spectrum for imaging in live mammals. A bottleneck slowing down structure-based drug development is the paucity of BACE crystal structures and the complete absence of structures for presenilin-inhibitor complexes.

Recommendations:

1. Develop bioluminescence assays to screen drug libraries for compounds affecting tau/Aβ

2. Encourage qualified structural biologists to seek crystal structures of the presenilin complex, providing a foundation for structure-based drug design.

3. Investigate pathway around presenilin to look for components that are more suitable as drug targets.

4. Use worm and fly to study control of synthesis, assembly, trafficking, and specificity of β-secretase complex. Better understanding of presenilin biology will be essential to assess therapeutic index of γ-secretase inhibitors and overcome industry reservations.

—Gabrielle Strobel ,June Kinoshita