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Inhibiting and Remodeling Toxic Amyloid-Beta Oligomer Formation Using a Computationally Designed Drug Molecule That Targets Alzheimer’s Disease

  • Matthew A. Downey
  • Maxwell J. Giammona
  • Christian A. Lang
  • Steven K. Buratto
  • Ambuj Singh
  • Michael T. Bowers
Focus: Honoring Carol V. Robinson's Election to the National Academy of Sciences: Research Article

Abstract

Alzheimer’s disease (AD) is rapidly reaching epidemic status among a burgeoning aging population. Much evidence suggests the toxicity of this amyloid disease is most influenced by the formation of soluble oligomeric forms of amyloid β-protein, particularly the 42-residue alloform (Aβ42). Developing potential therapeutics in a directed, streamlined approach to treating this disease is necessary. Here we utilize the joint pharmacophore space (JPS) model to design a new molecule [AC0107] incorporating structural characteristics of known Aβ inhibitors, blood-brain barrier permeability, and limited toxicity. To test the molecule’s efficacy experimentally, we employed ion mobility mass spectrometry (IM-MS) to discover [AC0107] inhibits the formation of the toxic Aβ42 dodecamer at both high (1:10) and equimolar concentrations of inhibitor. Atomic force microscopy (AFM) experiments reveal that [AC0107] prevents further aggregation of Aβ42, destabilizes preformed fibrils, and reverses Aβ42 aggregation. This trend continues for long-term interaction times of 2 days until only small aggregates remain with virtually no fibrils or higher order oligomers surviving. Pairing JPS with IM-MS and AFM presents a powerful and effective first step for AD drug development.

Graphical Abstract

Keywords

Aggregation Amyloid-β protein Aβ42 Ion mobility mass spectrometry Atomic force microscopy Inhibition Joint pharmacophore space Alzheimer’s disease 

Notes

Funding Information

The authors gratefully acknowledge support from the National Institute of Health – National Institute of Aging under grant 1R01AG047116 (M.T.B.) and funding through MURI and DURIP programs of the U.S. Army Research Office under Grant Nos. DAAD 19-03-1-0121 and W911NF-09-1-0280 for the purchase of the AFM instrument (S.K.B.).

Supplementary material

13361_2018_1975_MOESM1_ESM.pdf (600 kb)
ESM 1 (PDF 600 kb)

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Copyright information

© American Society for Mass Spectrometry 2018

Authors and Affiliations

  • Matthew A. Downey
    • 1
  • Maxwell J. Giammona
    • 1
  • Christian A. Lang
    • 2
  • Steven K. Buratto
    • 1
  • Ambuj Singh
    • 2
    • 3
  • Michael T. Bowers
    • 1
  1. 1.Department of Chemistry and BiochemistryUniversity of CaliforniaSanta BarbaraUSA
  2. 2.Acelot, Inc.Santa BarbaraUSA
  3. 3.Department of Computer ScienceUniversity of CaliforniaSanta BarbaraUSA

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