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Associating a negatively charged GdDOTA-derivative to the Pittsburgh compound B for targeting Aβ amyloid aggregates

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Abstract

We have conjugated the tetraazacyclododecane-tetraacetate (DOTA) chelator to Pittsburgh compound B (PiB) forming negatively charged lanthanide complexes, Ln(L4), with targeting capabilities towards aggregated amyloid peptides. The amphiphilic Gd(L4) chelate undergoes micellar aggregation in aqueous solution, with a critical micellar concentration of 0.68 mM, lower than those for the neutral complexes of similar structure. A variable temperature 17O NMR and NMRD study allowed the assessment of the water exchange rate, k 298ex  = 9.7 × 106 s−1, about the double of GdDOTA, and for the description of the rotational dynamics for both the monomeric and the micellar forms of Gd(L4). With respect to the analogous neutral complexes, the negative charge induces a significant rigidity of the micelles formed, which is reflected by slower and more restricted local motion of the Gd3+ centers as evidenced by higher relaxivities at 20–60 MHz. Surface Plasmon Resonance results indicate that the charge does not affect significantly the binding strength to Aβ1–40 [K d = 194 ± 11 μM for La(L4)], but it does enhance the affinity constant to human serum albumin [K a = 6530 ± 68 M−1 for Gd(L4)], as compared to neutral counterparts. Protein-based NMR points to interaction of Gd(L4) with Aβ1–40 in the monomer state as well, in contrast to neutral complexes interacting only with the aggregated form. Circular dichroism spectroscopy monitored time- and temperature-dependent changes of the Aβ1–40 secondary structure, indicating that Gd(L4) stabilizes the random coil relative to the α-helix and β-sheet. TEM images confirm that the Gd(L4) complex reduces the formation of aggregated fibrils.

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Acknowledgments

This work was supported by the Portuguese Fundação para a Ciência e Tecnologia (FCT; grants SFRH/BD/46370/2008 to A. F. M., REEQ/481/QUI/2006, RECI/QEQ-QFI/0168/2012 and CENTRO-07-CT62-FEDER-002012), by the Coimbra Chemistry Centre (project PEst-OE/QUI/UI0313/2014), the Rede Nacional de RMN (REDE/1517/RMN/2005), in part by FEDER—European Regional Development Fund through the COMPETE Program (Operational Program for Competitiveness) and by the French-Portuguese PHC PESSOA project. E. T. acknowledges support from La Ligue contre le Cancer and D. V. L. the support of the Spanish Ministry of Science and Innovation grants CTQ 2010-21567-C02-02 and SAF2013-49179-C2-2-R. This work was carried out in the frame of the European COST Actions TD1004 “Theragnostics Imaging and Therapy” and TD1007 “PET-MRI”.

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Author notes

  1. André F. Martins

    Present address: Department of Chemistry, University of Texas at Dallas, Richardson, TX, 75083, USA

Authors and Affiliations

  1. Centre de Biophysique Moléculaire, CNRS, UPR 4301, Université d’Orléans, Rue Charles Sadron, 45071, Orléans Cedex 2, France

    André F. Martins, Jean-François Morfin & Éva Tóth

  2. Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Calçada Martim de Freitas, 3000-393, Coimbra, Portugal

    André F. Martins & Carlos F. G. C. Geraldes

  3. Coimbra Chemistry Center, University of Coimbra, Rua Larga, 3004-535, Coimbra, Portugal

    André F. Martins, Alexandre C. Oliveira & Carlos F. G. C. Geraldes

  4. Instituto de Química Física “Rocasolano”, C.S.I.C., Serrano 119, 28006, Madrid, Spain

    Douglas V. Laurents

Authors
  1. André F. Martins
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  2. Alexandre C. Oliveira
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  3. Jean-François Morfin
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  4. Douglas V. Laurents
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  5. Éva Tóth
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  6. Carlos F. G. C. Geraldes
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Corresponding author

Correspondence to Carlos F. G. C. Geraldes.

Additional information

Dedicated to the memory of Professor Robert J. P. Williams.

Electronic supplementary material

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775_2015_1316_MOESM1_ESM.pdf

Supplementary material 1 (PDF 5803 kb) 1H Aβ1-40 line width changes in the presence of Gd(L4) (Figure S1), far-UV CD spectra of 40 μM Aβ1-40 in 10 mM sodium phosphate buffer, pH 7.3 as a function of time (Figure S2), equations for the analysis of 1H NMRD and 17O NMR data

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Martins, A.F., Oliveira, A.C., Morfin, JF. et al. Associating a negatively charged GdDOTA-derivative to the Pittsburgh compound B for targeting Aβ amyloid aggregates. J Biol Inorg Chem 21, 83–99 (2016). https://doi.org/10.1007/s00775-015-1316-9

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  • DOI: https://doi.org/10.1007/s00775-015-1316-9

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