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

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Organometallic DNA–B12 Conjugates as Potential Oligonucleotide Vectors : Synthesis and Structural and Binding Studies with Human Cobalamin-Transport Proteins. / Mutti, Elena; Hunger, Miriam; Fedosov, Sergey; Nexo, Ebba; Kräutler, Bernhard.

In: ChemBioChem, Vol. 18, No. 22, 16.11.2017, p. 2280-2291.

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@article{fc68519b2d784844bae49023b4766957,
title = "Organometallic DNA–B12 Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin-Transport Proteins",
abstract = "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.",
keywords = "bioinorganic chemistry, DNA, drug delivery, oligonucleotides, vitamins",
author = "Elena Mutti and Miriam Hunger and Sergey Fedosov and Ebba Nexo and Bernhard Kr{\"a}utler",
year = "2017",
month = "11",
day = "16",
doi = "10.1002/cbic.201700472",
language = "English",
volume = "18",
pages = "2280--2291",
journal = "ChemBioChem",
issn = "1439-4227",
publisher = "Wiley - V C H Verlag GmbH & Co. KGaA",
number = "22",

}

RIS

TY - JOUR

T1 - Organometallic DNA–B12 Conjugates as Potential Oligonucleotide Vectors

T2 - Synthesis and Structural and Binding Studies with Human Cobalamin-Transport Proteins

AU - Mutti, Elena

AU - Hunger, Miriam

AU - Fedosov, Sergey

AU - Nexo, Ebba

AU - Kräutler, Bernhard

PY - 2017/11/16

Y1 - 2017/11/16

N2 - 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.

AB - 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.

KW - bioinorganic chemistry

KW - DNA

KW - drug delivery

KW - oligonucleotides

KW - vitamins

UR - http://www.scopus.com/inward/record.url?scp=85033802756&partnerID=8YFLogxK

U2 - 10.1002/cbic.201700472

DO - 10.1002/cbic.201700472

M3 - Journal article

C2 - 28881087

AN - SCOPUS:85033802756

VL - 18

SP - 2280

EP - 2291

JO - ChemBioChem

JF - ChemBioChem

SN - 1439-4227

IS - 22

ER -