Design and development of drugs for Alzheimer's dementia as a protein misfolding disorder. (3rd June 2015)

• Record Type: Journal Article
• Authors: Barden, C; Meier-Stephenson, F; Carter, MD; Banfield, S; Diez, EC; Kelly, B; Lu, E; Meek, A; Meier-Stephenson, V; Pan, L; Simms, GA; Sweeting, B; Wang, Y; Wu, F; Yadav, A; Yang, S; Taylor, M; Reed, M; Weaver, DF
• Is Part Of: Canadian journal of neurological sciences. Volume 42:(2015)Supplement 1
• Page Start: S16
• Page End: S16
• Publication Date: 2015-06-03
• Subjects: Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Electronic journals; 616.8
• DOI: 10.1017/cjn.2015.95
• Languages: English
• ISSNs: 0317-1671

Abstract

Abstract : Background: There are no disease modifying agents for the treatment of Alzheimer's disease (AD). Pathologically, AD is associated with the misfolding of two peptides: beta-amyloid (plaques) and tau (tangles). Methods: Using large-scale computer simulations, we modelled the misfolding of both beta-amyloid and tau, identifying a common conformational motif (CCM; i.e. an abnormal peptide shape), present in both beta-amyloid and tau, that promotes their misfolding. We screened a library of 11.8 million compounds against this in silico model of protein misfolding, identifying three novel molecular classes of putative therapeutics as anti-protein misfolding agents. We synthesized approximately 400 new chemical entity drug-like molecules in each of these three classes (i.e. 1200 potential drug candidates). These were comprehensively screened in a battery of five in vitro protein oligomerization assays. Selected compounds were next evaluated in the APP/PS1 doubly transgenic mouse model of AD. Results: Two new classes of molecules were identified with the ability to block the oligomerization of both beta-amyloid and tau. These compounds are drug-like with good pharmacokinetic properties and are brain-penetrant. They exhibit excellent efficacy in transgenic mouse models. Conclusion: Computer aided drug design has enabled the discovery of novel drug-like molecules able to inhibit both tau and beta-amyloid misfolding.