Finding the Right Candidate for the Right Position: A Fast NMR-Assisted Combinatorial Method for Optimizing Nucleic Acids Binders

  1. Jiménez-Moreno, E. 6
  2. Montalvillo-Jiménez, Laura. 6
  3. Santana, A.G. 6
  4. Gómez, A.M. 6
  5. Jiménez-Osés, G. 45
  6. Corzana, F. 4
  7. Bastida, A. 6
  8. Jiménez-Barbero, J. 123
  9. Canada, F.J. 3
  10. Gómez-Pinto, I. 5
  11. González, C. 5
  12. Asensio, J.L. 6
  1. 1 Basque Foundation for Science, Ikerbasque, Bilbao, Bizkaia, Spain
  2. 2 Center for Cooperative Research in Biosciences (CIC-bioGUNE), Derio, Bizkaia, Spain
  3. 3 Centro de Investigaciones Biológicas
    info

    Centro de Investigaciones Biológicas

    Madrid, España

    ROR https://ror.org/04advdf21

  4. 4 Universidad de La Rioja
    info

    Universidad de La Rioja

    Logroño, España

    ROR https://ror.org/0553yr311

  5. 5 Instituto de Química Física Rocasolano
    info

    Instituto de Química Física Rocasolano

    Madrid, España

    ROR https://ror.org/03xk60j79

  6. 6 Instituto de Química Orgánica General
    info

    Instituto de Química Orgánica General

    Madrid, España

    ROR https://ror.org/05e0q7s59

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Zeitschrift:
Journal of the American Chemical Society

ISSN: 0002-7863

Datum der Publikation: 2016

Ausgabe: 138

Nummer: 20

Seiten: 6463-6474

Art: Artikel

DOI: 10.1021/JACS.6B00328 SCOPUS: 2-s2.0-84971432370 WoS: WOS:000376825900032 GOOGLE SCHOLAR

Andere Publikationen in: Journal of the American Chemical Society

Projekte im Zusammenhang

Financiación Adicional RAMÓN Y CAJAL G.J.O.

2015/00062/001

Una metodología computacional multi-escala para la modificación selectiva de proteínas y la reprogamación de enzimas.

2016/00015/001

Diseño estructural de glicopeptidos de tipo mucina que incorporan miméticos del antigeno TN para desarrollar biomarcadores y vacunas contra el cáncer.

2016/00001/001

Zusammenfassung

Development of strong and selective binders from promiscuous lead compounds represents one of the most expensive and time-consuming tasks in drug discovery. We herein present a novel fragment-based combinatorial strategy for the optimization of multivalent polyamine scaffolds as DNA/RNA ligands. Our protocol provides a quick access to a large variety of regioisomer libraries that can be tested for selective recognition by combining microdialysis assays with simple isotope labeling and NMR experiments. To illustrate our approach, 20 small libraries comprising 100 novel kanamycin-B derivatives have been prepared and evaluated for selective binding to the ribosomal decoding A-Site sequence. Contrary to the common view of NMR as a low-throughput technique, we demonstrate that our NMR methodology represents a valuable alternative for the detection and quantification of complex mixtures, even integrated by highly similar or structurally related derivatives, a common situation in the context of a lead optimization process. Furthermore, this study provides valuable clues about the structural requirements for selective A-site recognition. © 2016 American Chemical Society.