Functionalized Acyclic (l)-Threoninol Nucleic Acid Four-Way Junction with High Stability In Vitro and In Vivo

Anders Märcher; Vipin Kumar; Veronica L. Andersen; Kassem El-Chami; Thuy J.D. Nguyen; Mads K. Skaanning; Imke Rudnik-Jansen; Jesper S. Nielsen; Kenneth A. Howard; Jørgen Kjems; Kurt V. Gothelf

doi:10.1002/anie.202115275

Functionalized Acyclic (l)-Threoninol Nucleic Acid Four-Way Junction with High Stability In Vitro and In Vivo

Anders Märcher, Vipin Kumar, Veronica L. Andersen, Kassem El-Chami, Thuy J.D. Nguyen, Mads K. Skaanning, Imke Rudnik-Jansen, Jesper S. Nielsen, Kenneth A. Howard, Jørgen Kjems, Kurt V. Gothelf^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Oligonucleotides are increasingly being used as a programmable connection material to assemble molecules and proteins in well-defined structures. For the application of such assemblies for in vivo diagnostics or therapeutics it is crucial that the oligonucleotides form highly stable, non-toxic, and non-immunogenic structures. Only few oligonucleotide derivatives fulfil all of these requirements. Here we report on the application of acyclic l-threoninol nucleic acid (aTNA) to form a four-way junction (4WJ) that is highly stable and enables facile assembly of components for in vivo treatment and imaging. The aTNA 4WJ is serum-stable, shows no non-targeted uptake or cytotoxicity, and invokes no innate immune response. As a proof of concept, we modify the 4WJ with a cancer-targeting and a serum half-life extension moiety and show the effect of these functionalized 4WJs in vitro and in vivo, respectively.

Original language	English
Article number	202115275
Journal	Angewandte Chemie - International Edition
Volume	61
Issue	24
Number of pages	7
ISSN	1433-7851
DOIs	https://doi.org/10.1002/anie.202115275
Publication status	Published - Jun 2022

Keywords

aTNA
DNA
Holliday Junction
Nanostructures
CELLS
NANOBODIES
DNA NANOSTRUCTURES
PROTEINS
DELIVERY
Butylene Glycols
Nucleic Acids/chemistry
Oligonucleotides
RNA/chemistry
Amino Alcohols/chemistry
Nucleic Acid Conformation

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Märcher, A., Kumar, V., Andersen, V. L., El-Chami, K., Nguyen, T. J. D., Skaanning, M. K., Rudnik-Jansen, I., Nielsen, J. S., Howard, K. A., Kjems, J., & Gothelf, K. V. (2022). Functionalized Acyclic (l)-Threoninol Nucleic Acid Four-Way Junction with High Stability In Vitro and In Vivo. Angewandte Chemie - International Edition, 61(24), Article 202115275. https://doi.org/10.1002/anie.202115275

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title = "Functionalized Acyclic (l)-Threoninol Nucleic Acid Four-Way Junction with High Stability In Vitro and In Vivo",

abstract = "Oligonucleotides are increasingly being used as a programmable connection material to assemble molecules and proteins in well-defined structures. For the application of such assemblies for in vivo diagnostics or therapeutics it is crucial that the oligonucleotides form highly stable, non-toxic, and non-immunogenic structures. Only few oligonucleotide derivatives fulfil all of these requirements. Here we report on the application of acyclic l-threoninol nucleic acid (aTNA) to form a four-way junction (4WJ) that is highly stable and enables facile assembly of components for in vivo treatment and imaging. The aTNA 4WJ is serum-stable, shows no non-targeted uptake or cytotoxicity, and invokes no innate immune response. As a proof of concept, we modify the 4WJ with a cancer-targeting and a serum half-life extension moiety and show the effect of these functionalized 4WJs in vitro and in vivo, respectively.",

keywords = "aTNA, DNA, Holliday Junction, Nanostructures, CELLS, NANOBODIES, DNA NANOSTRUCTURES, PROTEINS, DELIVERY, Butylene Glycols, Nucleic Acids/chemistry, Oligonucleotides, RNA/chemistry, Amino Alcohols/chemistry, Nucleic Acid Conformation",

author = "Anders M{\"a}rcher and Vipin Kumar and Andersen, {Veronica L.} and Kassem El-Chami and Nguyen, {Thuy J.D.} and Skaanning, {Mads K.} and Imke Rudnik-Jansen and Nielsen, {Jesper S.} and Howard, {Kenneth A.} and J{\o}rgen Kjems and Gothelf, {Kurt V.}",

note = "{\textcopyright} 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.",

year = "2022",

month = jun,

doi = "10.1002/anie.202115275",

language = "English",

volume = "61",

journal = "Angewandte Chemie - International Edition",

issn = "1433-7851",

publisher = "Wiley - VCH Verlag GmbH & CO. KGaA",

number = "24",

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Märcher, A, Kumar, V, Andersen, VL, El-Chami, K, Nguyen, TJD, Skaanning, MK, Rudnik-Jansen, I, Nielsen, JS, Howard, KA , Kjems, J & Gothelf, KV 2022, 'Functionalized Acyclic (l)-Threoninol Nucleic Acid Four-Way Junction with High Stability In Vitro and In Vivo', Angewandte Chemie - International Edition, vol. 61, no. 24, 202115275. https://doi.org/10.1002/anie.202115275

Functionalized Acyclic (l)-Threoninol Nucleic Acid Four-Way Junction with High Stability In Vitro and In Vivo. / Märcher, Anders; Kumar, Vipin; Andersen, Veronica L. et al.
In: Angewandte Chemie - International Edition, Vol. 61, No. 24, 202115275, 06.2022.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Functionalized Acyclic (l)-Threoninol Nucleic Acid Four-Way Junction with High Stability In Vitro and In Vivo

AU - Märcher, Anders

AU - Kumar, Vipin

AU - Andersen, Veronica L.

AU - El-Chami, Kassem

AU - Nguyen, Thuy J.D.

AU - Skaanning, Mads K.

AU - Rudnik-Jansen, Imke

AU - Nielsen, Jesper S.

AU - Howard, Kenneth A.

AU - Kjems, Jørgen

AU - Gothelf, Kurt V.

PY - 2022/6

Y1 - 2022/6

N2 - Oligonucleotides are increasingly being used as a programmable connection material to assemble molecules and proteins in well-defined structures. For the application of such assemblies for in vivo diagnostics or therapeutics it is crucial that the oligonucleotides form highly stable, non-toxic, and non-immunogenic structures. Only few oligonucleotide derivatives fulfil all of these requirements. Here we report on the application of acyclic l-threoninol nucleic acid (aTNA) to form a four-way junction (4WJ) that is highly stable and enables facile assembly of components for in vivo treatment and imaging. The aTNA 4WJ is serum-stable, shows no non-targeted uptake or cytotoxicity, and invokes no innate immune response. As a proof of concept, we modify the 4WJ with a cancer-targeting and a serum half-life extension moiety and show the effect of these functionalized 4WJs in vitro and in vivo, respectively.

AB - Oligonucleotides are increasingly being used as a programmable connection material to assemble molecules and proteins in well-defined structures. For the application of such assemblies for in vivo diagnostics or therapeutics it is crucial that the oligonucleotides form highly stable, non-toxic, and non-immunogenic structures. Only few oligonucleotide derivatives fulfil all of these requirements. Here we report on the application of acyclic l-threoninol nucleic acid (aTNA) to form a four-way junction (4WJ) that is highly stable and enables facile assembly of components for in vivo treatment and imaging. The aTNA 4WJ is serum-stable, shows no non-targeted uptake or cytotoxicity, and invokes no innate immune response. As a proof of concept, we modify the 4WJ with a cancer-targeting and a serum half-life extension moiety and show the effect of these functionalized 4WJs in vitro and in vivo, respectively.

KW - aTNA

KW - DNA

KW - Holliday Junction

KW - Nanostructures

KW - CELLS

KW - NANOBODIES

KW - DNA NANOSTRUCTURES

KW - PROTEINS

KW - DELIVERY

KW - Butylene Glycols

KW - Nucleic Acids/chemistry

KW - Oligonucleotides

KW - RNA/chemistry

KW - Amino Alcohols/chemistry

KW - Nucleic Acid Conformation

UR - http://www.scopus.com/inward/record.url?scp=85128196548&partnerID=8YFLogxK

U2 - 10.1002/anie.202115275

DO - 10.1002/anie.202115275

M3 - Journal article

C2 - 35352451

AN - SCOPUS:85128196548

SN - 1433-7851

VL - 61

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

IS - 24

M1 - 202115275

ER -

Functionalized Acyclic (l)-Threoninol Nucleic Acid Four-Way Junction with High Stability In Vitro and In Vivo

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Keywords

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