Final Report Summary - BEAUVERIOLIDE (Beauveriolide-derived cyclodepsipeptides as a new class of anti-Alzheimer's drugs)
The pathogenic event common to all forms of Alzheimer's disease (AD) is the abnormal accumulation of the amyloid beta-peptide (amyloid-beta (Abeta)) in specific regions of the brain. This accumulation of Abeta is considered a key pathological event in AD and is the basis of the so-called amyloid hypothesis of the disease. Therefore, therapeutic approaches that reduce the accumulation of Abeta are currently being sought. It has been definitively shown that the generation and clearance of Abeta in the central nervous system (CNS) is regulated by cholesterol homeostasis. Compounds that perturb cellular free cholesterol homeostasis such as acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors have been shown both in vitro and in vivo to reduce Abeta production and secretion. However, it is generally the case that ACAT inhibitors exhibit poor oral activity. The beauveriolides are a new class of fungal metabolites that have been shown to be orally active ACAT inhibitors and are currently being investigated as potential therapeutics for atherosclerosis. Therefore, certainly in the context of atherosclerosis and now with ad, there is an unmet need for potent ACAT inhibitors with good bioavailability.
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.
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.