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Modulating Self-Assembly of Amyloidogenic Proteins as a Therapeutic Approach for Neurodegenerative Diseases: Strategies and Mechanisms

  1. Tingyu Liu2,
  2. Dr. Gal Bitan1,*

Article first published online: 9 FEB 2012

DOI: 10.1002/cmdc.201100585

Issue

ChemMedChem

ChemMedChem

Special Issue: Neuroscience Drug Discovery

Volume 7, Issue 3, pages 359–374, March 5, 2012

Additional Information

How to Cite

Liu, T. and Bitan, G. (2012), Modulating Self-Assembly of Amyloidogenic Proteins as a Therapeutic Approach for Neurodegenerative Diseases: Strategies and Mechanisms. ChemMedChem, 7: 359–374. doi: 10.1002/cmdc.201100585

Author Information

  1. 1

    Department of Neurology, David Geffen School of Medicine, and Brain Research Institute and Molecular Biology Institute, University of California, Los Angeles, 635 Charles E. Young Drive South/NRB 455, Los Angeles, CA 90095 (USA)

  2. 2

    Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 635 Charles E. Young Drive South/NRB 455, Los Angeles, CA 90095 (USA)

*Department of Neurology, David Geffen School of Medicine, and Brain Research Institute and Molecular Biology Institute, University of California, Los Angeles, 635 Charles E. Young Drive South/NRB 455, Los Angeles, CA 90095 (USA)

Publication History

  1. Issue published online: 1 MAR 2012
  2. Article first published online: 9 FEB 2012
  3. Manuscript Received: 11 DEC 2011

Funded by

  • University of California, Los Angeles (UCLA) Jim Easton Consortium for Alzheimer’s Drug Discovery and Biomarker Development
  • California Department of Health Services (USA). Grant Number: 07-65798
  • Team Parkinson/Parkinson Alliance (Kingston, USA)
  • RJG Foundation (New York, USA). Grant Number: 20095024
  • Cure Alzheimer’s Fund (USA)

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Keywords:

  • aggregation;
  • amyloid proteins;
  • drug design;
  • inhibitors;
  • molecular tweezers;
  • oligomerization;
  • polyphenols

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.

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