Final Report Summary - BEAUVERIOLIDE (Beauveriolide-derived cyclodepsipeptides as a new class of anti-Alzheimer's drugs)
It is the rationale of this proposal, entitled 'Beauveriolide-derived cyclodepsipeptides as a new class of anti-Alzheimer's drug', that given that the beauveriolides are orally active inhibitors of ACAT-1 (as well as ACAT-2), that they should be investigated and optimised structurally for their ability to reduce Abeta production in vitro.
It has two main objectives:
1. synthesis of beauveriolide-derived cyclodepsipeptide and cyclopeptide libraries;
2. determine whether synthetic beauveriolide-inspired libraries reduce the levels of beta-secretase cleavage products of APP, including Abeta in vitro. The proposed libraries of derivatives have been prepared accumulating more than 60 compounds of beauveriolide I and III inspired compounds. In addition, a more efficient synthetic sequence to prepare this family of compound has been developed. Compounds have been tested in vitro to assess their ability to either reduce lipid loading by ACAT inhibition and / or reduce Abeta production and secretion. Allowing us to confirm the hypothesis initially formulated in the proposal, that natural product beauveriolides or beauveriolide-inspired libraries of compounds should reduce Abeta production and secretion in vitro via inhibition of ACAT and hence perturbation of cholesterol homeostasis.