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Metal coordination and peripheral substitution modulate the activity of cyclic tetrapyrroles on αS aggregation: a structural and cell-based study

  • Nazareno González
  • Iñaki Gentile
  • Hugo A. Garro
  • Susana Delgado-Ocaña
  • Carla F. Ramunno
  • Fiamma A. Buratti
  • Christian Griesinger
  • Claudio O. FernándezEmail author
Original Paper
Part of the following topical collections:
  1. Metal Ions and Degenerative Diseases

Abstract

The discovery of aggregation inhibitors and the elucidation of their mechanism of action are key in the quest to mitigate the toxic consequences of amyloid formation. We have previously characterized the antiamyloidogenic mechanism of action of sodium phtalocyanine tetrasulfonate ([Na4(H2PcTS)]) on α-Synuclein (αS), demonstrating that specific aromatic interactions are fundamental for the inhibition of amyloid assembly. Here we studied the influence that metal preferential affinity and peripheral substituents may have on the activity of tetrapyrrolic compounds on αS aggregation. For the first time, our laboratory has extended the studies in the field of the bioinorganic chemistry and biophysics to cellular biology, using a well-established cell-based model to study αS aggregation. The interaction scenario described in our work revealed that both N- and C-terminal regions of αS represent binding interfaces for the studied compounds, a behavior that is mainly driven by the presence of negatively or positively charged substituents located at the periphery of the macrocycle. Binding modes of the tetrapyrrole ligands to αS are determined by the planarity and hydrophobicity of the aromatic ring system in the tetrapyrrolic molecule and/or the preferential affinity of the metal ion conjugated at the center of the macrocyclic ring. The different capability of phthalocyanines and meso-tetra (N-methyl-4-pyridyl) porphine tetrachloride ([H2PrTPCl4]) to modulate αS aggregation in vitro was reproduced in cell-based models of αS aggregation, demonstrating unequivocally that the modulation exerted by these compounds on amyloid assembly is a direct consequence of their interaction with the target protein.

Keywords

Misfolding Amyloid Neurodegeneration Inhibitors 

Notes

Acknowledgements

C.O.F. thanks Universidad Nacional de Rosario (UNR) and ANPCyT- FONCyT (PICT 2014-3704 and PICT 2017-4665) for financial support. C.O.F. and C.G. thank the Max Planck Society (P10390) for support. C.O.F thanks Dietmar Riedel and Gudrum Heim for helpful assistance during the transmission electron microscopy measurements. N.G. and I.G. thanks UNR for fellowships. F.B. thanks CONICET for fellowship.

Supplementary material

775_2019_1711_MOESM1_ESM.pdf (585 kb)
Supplementary material 1 (PDF 584 kb)

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Copyright information

© Society for Biological Inorganic Chemistry (SBIC) 2019

Authors and Affiliations

  • Nazareno González
    • 1
  • Iñaki Gentile
    • 1
  • Hugo A. Garro
    • 1
    • 2
  • Susana Delgado-Ocaña
    • 1
  • Carla F. Ramunno
    • 1
  • Fiamma A. Buratti
    • 1
  • Christian Griesinger
    • 3
  • Claudio O. Fernández
    • 1
    • 3
    Email author
  1. 1.Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC) and Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR, UNR-CONICET)Universidad Nacional de RosarioRosarioArgentina
  2. 2.Facultad de Química, Bioquímica y FarmaciaUniversidad Nacional de San LuisSan LuisArgentina
  3. 3.Department of NMR-based Structural BiologyMax Planck Institute for Biophysical ChemistryGöttingenGermany

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