Rational design of amyloid beta-protein aggregation and toxicity inhibitors

Principal Investigator

Project Goals

In this project we will use a novel approach that combines our most current understanding of the molecular processes that lead to AD. We do that by "tailoring" sophisticated weapons that target what is believed to be the very first event along the pathway that leads to formation of the toxic molecules that rob AD patients of their memory and personality.

Project Summary

Alzheimer's disease (AD) is a current major public health threat, which despite tremendous research efforts, to date has no cure. To cure and prevent the disease we must invent drugs that treat the root of the problem. In this project we will use a novel approach that combines our most current understanding of the molecular processes that lead to AD. We do that by "tailoring" sophisticated weapons that target what is believed to be the very first event along the pathway that leads to formation of the toxic molecules that rob AD patients of their memory and personality. Unlike the direction used by most pharmaceutical companies - screening of large, random collections of molecules,our study is the first example of using a rational-design approach that is based on the three-dimensional structure of the toxic protein that causes AD.

Publications

Hochdörffer K, März-Berberich J, Nagel-Steger L, Epple M, Meyer-Zaika W, Horn AH, Sticht H, Sinha S, Bitan G, Schrader T.J. Am Chem Soc. (2011) Rational Design of β-Sheet Ligands Against Aβ(42)-Induced Toxicity. 2011 Mar 30;133(12):4348-4358. Epub 2011 Mar 7. PubMed Icon Google Scholar Icon

Sharmistha Sinha, Dahabada H. J. Lopes, and Gal Bitan. A Key Role for Lysine Residues in Amyloid #- Protein Folding, Assembly, and Toxicity ACS Chem. Neurosci., [PMID: nd]

Sharmistha Sinha,õ Zhenming Du,a Panchanan Maiti,õ Frank-Gerrit Kla.rner,Û Thomas Schrader,Û Chunyu Wang,a and Gal Bitan*. Comparison of Three Amyloid Assembly Inhibitors: The Sugar scyllo- Inositol, the Polyphenol Epigallocatechin Gallate, and the Molecular Tweezer CLR01 [PMID:nd]

Sinha S, Lopes DH, Du Z, Pang ES, Shanmugam A, Lomakin A, Talbiersky P, Tennstaedt A, McDaniel K, Bakshi R, Kuo PY, Ehrmann M, Benedek GB, Loo JA, Klärner FG, Schrader T, Wang C, Bitan G.J. Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins. Am Chem Soc. 2011 Oct 26;133(42):16958-69. Epub 2011 Sep 29. PubMed Icon Google Scholar Icon
 

First published on: June 11, 2008

Last modified on: February 25, 2024