IBR   13079
INSTITUTO DE BIOLOGIA MOLECULAR Y CELULAR DE ROSARIO
Unidad Ejecutora - UE
artículos
Título:
Towards the discovery of effective polycyclic inhibitors of alpha-Synuclein amyloid assembly
Autor/es:
GONZALO R. LAMBERTO; VALENTINA TORRES-MONSERRAT; CARLOS W. BERTONCINI; XAVIER SALVATELLA; MARKUS ZWECKSTETTER; CHRISTIAN GRIESINGER; CLAUDIO O. FERNANDEZ
Revista:
JOURNAL OF BIOLOGICAL CHEMISTRY
Editorial:
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Referencias:
Lugar: Bethesda, Maryland; Año: 2011 vol. 286 p. 32036 - 32044
ISSN:
0021-9258
Resumen:
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)] , PcTS >
PcTS[Zn(II)] > PcTS[Al(III)] ¡Ö 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.