Metal ion controlled self-assembly of a chemically reengineered protein drug studied by small-angle X-ray scattering

Publication: Research - peer-reviewJournal article – Annual report year: 2012

  • Author: Jesper, Nygaard, Denmark

    Niels Bohr Institute, University of Copenhagen, Denmark

  • Author: Munch, Henrik K. , Denmark

    Department of Chemistry, University of Copenhagen, Denmark

  • Author: Thulstrup, Peter W. , Denmark

    Department of Chemistry, University of Copenhagen, Denmark

  • Author: Christensen, Niels Johan

    Physical and Biophysical Chemistry, Department of Chemistry, Technical University of Denmark, Kemitorvet, 2800, Kgs. Lyngby, Denmark

  • Author: Hoeg-Jensen, Thomas, Denmark

    Diabetes Protein and Peptide Chemistry, Novo Nordisk, Denmark

  • Author: Jensen, Knud J. , Denmark

    Department of Chemistry, University of Copenhagen, Denmark

  • Author: Arleth, Lise , Denmark

    Niels Bohr Institute, University of Copenhagen, Denmark

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Precise control of the oligomeric state of proteins is of central importance for biological function and for the properties of biopharmaceutical drugs. Here, the self-assembly of 2,2′-bipyridine conjugated monomeric insulin analogues, induced through coordination to divalent metal ions, was studied. This protein drug system was designed to form non-native homo-oligomers through selective coordination of two divalent metal ions, Fe(II) and Zn(II), respectively. The insulin type chosen for this study is a variant designed for a reduced tendency toward native dimer formation at physiological concentrations. A small-angle X-ray scattering analysis of the bipyridine-modified insulin system confirmed an organization into a novel well-ordered structure based on insulin trimers, as induced by the addition of Fe(II). In contrast, unmodified monomeric insulin formed larger and more randomly structured assemblies upon addition of Fe(II). The addition of Zn(II), on the other hand, led to the formation of small quantities of insulin hexamers for both the bipyridine-modified and the unmodified monomeric insulin. Interestingly, the location of the bipyridine-modification significantly affects the tendency to hexamer formation as compared to the unmodified insulin. Our study shows how combining a structural study and chemical design can be used to obtain molecular understanding and control of the self-assembly of a protein drug. This knowledge may eventually be employed to develop an optimized in vivo drug release profile.
Original languageEnglish
JournalLangmuir
Publication date2012
Volume28
Journal number33
Pages12159-12170
ISSN0743-7463
DOIs
StatePublished

Bibliographical note

© 2011 American Chemical Society

CitationsWeb of Science® Times Cited: 3

Keywords

  • Insulin, Protein Based Drugs, Protein Delivery, Drugdelivery, Self-assembly, Small-Angle Scattering
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