Author(s): Liu T, Bitan G
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Abstract Abnormal protein assembly causes multiple devastating disorders in the central nervous system (CNS), such as Alzheimer's, Parkinson's, Huntington's, and prion diseases. Due to the now extended human lifespan, these diseases have been increasing in prevalence, resulting in major public health problems and the associated financial difficulties worldwide. The wayward proteins that lead to disease self-associate into neurotoxic oligomers and go on to form fibrillar polymers through multiple pathways. Thus, a range of possible targets for pharmacotherapeutic intervention exists along these pathways. Many compounds have shown different levels of effectiveness in inhibiting aberrant self-assembly, dissociating existing aggregates, protecting cells against neurotoxic insults, and in some cases ameliorating disease symptoms in vivo, yet achieving efficient, disease-modifying therapy in humans remains a major unattained goal. To a large degree, this is because the mechanisms of action for these drugs are essentially unknown. For successful design of new effective drugs, it is crucial to elucidate the mechanistic details of their action, including the actual target(s) along the protein aggregation pathways, how the compounds modulate these pathways, and their effect at the cellular, tissue, organ, and organism level. Here, the current knowledge of major mechanisms by which some of the more extensively explored drug candidates work are discussed. In particular, we focus on three prominent strategies: 1) stabilizing the native fold of amyloidogenic proteins, 2) accelerating the aggregation pathways towards the fibrillar endpoint thereby reducing accumulation of toxic oligomers, and 3) modulating the assembly process towards nontoxic oligomers/aggregates. The merit of each strategy is assessed, and the key points to consider when analyzing the efficacy of possible drug candidates and their mechanism of action are discussed. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
This article was published in ChemMedChem
and referenced in Journal of Gerontology & Geriatric Research