Organometallic DNA–B12 Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin-Transport Proteins

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DOI

The synthesis and structural characterization of Co-(dN)25-Cbl (Cbl: cobalamin; dN: deoxynucleotide) and Co-(dN)39-Cbl, which are organometallic DNA–B12 conjugates with single DNA strands consisting of 25 and 39 deoxynucleotides, respectively, and binding studies of these two DNA–Cbl conjugates to three homologous human Cbl transporting proteins, transcobalamin (TC), intrinsic factor (IF), and haptocorrin (HC), are reported. This investigation tests the suitability of such DNA–Cbls for the task of eventual in vivo oligonucleotide delivery. The binding of DNA–Cbl to TC, IF, and HC was investigated in competition with either a fluorescent Cbl derivative and Co-(dN)25-Cbl, or radiolabeled vitamin B12 (57Co-CNCbl) and Co-(dN)25-Cbl or Co-(dN)39-Cbl. Binding of the new DNA–Cbl conjugates was fast and tight with TC, but poorer with HC and IF, which extends a similar original finding with the simpler DNA–Cbl, Co-(dN)18-Cbl. The contrasting affinities of TC versus IF and HC for the DNA–Cbl conjugates are rationalized herein by a stepwise mechanism of Cbl binding. Critical contributions to overall affinity result from gradual conformational adaptations of the Cbl-binding proteins to the DNA–Cbl, which is first bound to the respective β domains. This transition is fast with TC, but slow with IF and HC, with which weaker binding results. The invariably tight interaction of the DNA–Cbl conjugates with TC makes the Cbl moiety a potential natural vector for the specific delivery of oligonucleotide loads from the blood into cells.

Original languageEnglish
JournalChemBioChem
Volume18
Issue22
Pages (from-to)2280-2291
Number of pages12
ISSN1439-4227
DOIs
Publication statusPublished - 16 Nov 2017

    Research areas

  • bioinorganic chemistry, DNA, drug delivery, oligonucleotides, vitamins

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