Discovery of ADDL-Targeting Small Molecule Drugs for Alzheimers Disease

Title: Discovery of ADDL-Targeting Small Molecule Drugs for Alzheimers Disease

Volume: 4 Issue: 5

Author(s): Raymond M. Lowe, Grant A. Krafft, David Summa, William F. Goure, Susan M. Catalano, Sue Zhang, Hsiu-Mei Wu, Lily Ruslim-Litrus, Michele McEntee, Gary C. Look, Catherine M. Hironaka, Lev Igoudin, Walter J. Crosier, Jean-Claude R. Breach, Todd R. Pray, Diana B. Cherbavaz and Jasna Jerecic

Affiliation:

Keywords: ADDL, Alzheimer, amyloid, assembly, drug, inhibitor, neuron, oligomer

Abstract: Amyloid β-derived diffusible ligands (ADDLs) comprise the neurotoxic subset of soluble Aβ1-42 oligomers, now widely considered to be the molecular cause of memory malfunction and neurodegeneration in Alzheimers disease (AD). We have developed a screening cascade which identifies small molecule modulators of ADDL-mediated neurotoxicity. The primary screen involves a fluorescence resonance energy transfer (FRET)-based assay which selects inhibitors of Aβ1-42 oligomer assembly. The identified hits were further characterized by assessing their ability to inhibit the assembly and binding of ADDLs to cultures of primary hippocampal neurons. This approach has led to the identification of a number of small molecules which inhibit ADDL assembly and their subsequent binding to neurons. Here we describe our small molecule discovery efforts to identify ADDL assembly blocker and ADDL binding inhibitors, and to transform validated hits into pre-clinical lead compounds.

Cite this article as:

Lowe M. Raymond, Krafft A. Grant, Summa David, Goure F. William, Catalano M. Susan, Zhang Sue, Wu Hsiu-Mei, Ruslim-Litrus Lily, McEntee Michele, Look C. Gary, Hironaka M. Catherine, Igoudin Lev, Crosier J. Walter, Breach R. Jean-Claude, Pray R. Todd, Cherbavaz B. Diana and Jerecic Jasna, Discovery of ADDL-Targeting Small Molecule Drugs for Alzheimers Disease, Current Alzheimer Research 2007; 4 (5) . https://dx.doi.org/10.2174/156720507783018271