4.6 Article

Toward the Discovery of Effective Polycyclic Inhibitors of α-Synuclein Amyloid Assembly

期刊

JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 37, 页码 32036-32044

出版社

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.242958

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资金

  1. Agencia Nacional de Promocion Cientifica y Tecnologica, Argentina
  2. Fundacion Antorchas
  3. Max Planck Society
  4. Alexander von Humboldt Foundation
  5. Fundacion Josefina Prats
  6. Government of Santa Fe
  7. ANPCyT [PME2003-2006]
  8. Consejo Nacional de Investigaciones Cientificas y Tecnicas, Argentina (CONICET)
  9. CONICET in Argentina
  10. Framework Programme 7 Marie Curie Intra-European Fellowship
  11. Institucio Catalana de Recerca i Estudis Avancats
  12. Institute for Research in Biomedicine, Barcelona, Spain
  13. Ministerio de Ciencia e Innovacion de Espana [CTQ2009-08850-BQU]
  14. Max Planck Society, Federal Ministry of Education and Research, Germany [NGFN-Plus 01GS08190]
  15. Deutsche Forschungsgemeinschaft [ZW 71/2-2, 3-2]

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The fibrillation of amyloidogenic proteins is a critical step in the etiology of neurodegenerative disorders such as Alzheimer and Parkinson diseases. There is major interest in the therapeutic intervention on such aberrant aggregation phenomena, and the utilization of polyaromatic scaffolds has lately received considerable attention. In this regard, the molecular and structural basis of the anti-amyloidogenicity of polyaromatic compounds, required to evolve this molecular scaffold toward therapeutic drugs, is not known in detail. We present here biophysical and biochemical studies that have enabled us to characterize the interaction of metal-substituted, tetrasulfonated phthalocyanines (PcTS) with alpha-synuclein (AS), the major protein component of amyloid-like deposits in Parkinson disease. The inhibitory activity of the assayed compounds on AS amyloid fibril formation decreases in the order PcTS[Ni(II)] similar to PcTS > PcTS[Zn(II)] >> PcTS[Al(III)] approximate to 0. Using NMR and electronic absorption spectroscopies we demonstrated conclusively that the differences in binding capacity and anti-amyloid activity of phthalocyanines on AS are attributed to their relative ability to self-stack through pi-pi interactions, modulated by the nature of the metal ion bound at the molecule. Low order stacked aggregates of phthalocyanines were identified as the active amyloid inhibitory species, whose effects are mediated by residue specific interactions. Such sequence-specific anti-amyloid behavior of self-stacked phthalocyanines contrasts strongly with promiscuous amyloid inhibitors with self-association capabilities that act via nonspecific sequestration of AS molecules. The new findings reported here constitute an important contribution for future drug discovery efforts targeting amyloid formation.

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