Structural Insight into the Self-Assembly of a Pharmaceutically Optimized Insulin Analogue Obtained by Small-Angle X-ray Scattering

Research output: Contribution to journal › Journal article › Research › peer-review

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Structural Insight into the Self-Assembly of a Pharmaceutically Optimized Insulin Analogue Obtained by Small-Angle X-ray Scattering. / Dreyer, Lasse Sander; Nygaard, Jesper; Malik, Leila; Hoeg-Jensen, Thomas; Hoiberg-Nielsen, Rasmus; Arleth, Lise.

In: Molecular Pharmaceutics, Vol. 17, No. 8, 03.08.2020, p. 2809-2820.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Dreyer, LS, Nygaard, J, Malik, L, Hoeg-Jensen, T, Hoiberg-Nielsen, R & Arleth, L 2020, 'Structural Insight into the Self-Assembly of a Pharmaceutically Optimized Insulin Analogue Obtained by Small-Angle X-ray Scattering', Molecular Pharmaceutics, vol. 17, no. 8, pp. 2809-2820. https://doi.org/10.1021/acs.molpharmaceut.0c00112

APA

Dreyer, L. S., Nygaard, J., Malik, L., Hoeg-Jensen, T., Hoiberg-Nielsen, R., & Arleth, L. (2020). Structural Insight into the Self-Assembly of a Pharmaceutically Optimized Insulin Analogue Obtained by Small-Angle X-ray Scattering. Molecular Pharmaceutics, 17(8), 2809-2820. https://doi.org/10.1021/acs.molpharmaceut.0c00112

Vancouver

Dreyer LS, Nygaard J, Malik L, Hoeg-Jensen T, Hoiberg-Nielsen R, Arleth L. Structural Insight into the Self-Assembly of a Pharmaceutically Optimized Insulin Analogue Obtained by Small-Angle X-ray Scattering. Molecular Pharmaceutics. 2020 Aug 3;17(8):2809-2820. https://doi.org/10.1021/acs.molpharmaceut.0c00112

Author

Dreyer, Lasse Sander ; Nygaard, Jesper ; Malik, Leila ; Hoeg-Jensen, Thomas ; Hoiberg-Nielsen, Rasmus ; Arleth, Lise. / Structural Insight into the Self-Assembly of a Pharmaceutically Optimized Insulin Analogue Obtained by Small-Angle X-ray Scattering. In: Molecular Pharmaceutics. 2020 ; Vol. 17, No. 8. pp. 2809-2820.

Bibtex

@article{fab0e603deb64ae2aafa296095a2225f,
title = "Structural Insight into the Self-Assembly of a Pharmaceutically Optimized Insulin Analogue Obtained by Small-Angle X-ray Scattering",
abstract = "B29N(epsilon)-lithocholyl-gamma-L-beta Glu-desB30 human insulin [NN344] belongs to a group of insulins with fatty acid or sterol modifications. These insulin analogues have been found to form subcutaneous depots upon injection and hereby have a protracted release profile in vivo. In the present study, B29N(epsilon)-lithocholyl-gamma-L-Glu-desB30 human insulin was investigated using in-solution small-angle X-ray scattering (SAXS) at chemical conditions designed to mimic three stages during treatment in vivo: in-vial/pen, postinjection, and longer times after injection. We found that the specific insulin analogue formed a mixture of mono- and dihexamers under in-vial/pen conditions of low salt and stabilizing phenol. At postinjection, conditions mimicking a subcutaneous depot, B29N(epsilon)-lithocholyl-gamma-L-Glu-desB30 human insulin, formed very long straight soluble hexamer-based rods stacked along the Zn(II)-axis. The self-assembly was triggered by an increase in salt concentration when going from vial to physiological conditions. Mimicking longer times after injection and the additional removal of phenol caused the length of the rods to decrease significantly. Finally, we found that the self-assembly could be controlled by varying the amount of modification at the interaction interface by making mixed hexamers of B29N(epsilon)-lithocholyl-gamma-L-Glu-desB30 and desB30 human insulin. This opens extra possibilities for controlling the release profile of very-long-acting insulins.",
keywords = "insulin, SAXS, self-assembly, oligomer, prolonged action, ZINC-BINDING DOMAINS, MONOMERIC INSULINS, MECHANISM, PROTRACTION, DEGLUDEC, DETEMIR",
author = "Dreyer, {Lasse Sander} and Jesper Nygaard and Leila Malik and Thomas Hoeg-Jensen and Rasmus Hoiberg-Nielsen and Lise Arleth",
year = "2020",
month = aug,
day = "3",
doi = "10.1021/acs.molpharmaceut.0c00112",
language = "English",
volume = "17",
pages = "2809--2820",
journal = "Molecular Pharmaceutics",
issn = "1543-8384",
publisher = "American Chemical Society",
number = "8",

}

RIS

TY - JOUR

T1 - Structural Insight into the Self-Assembly of a Pharmaceutically Optimized Insulin Analogue Obtained by Small-Angle X-ray Scattering

AU - Dreyer, Lasse Sander

AU - Nygaard, Jesper

AU - Malik, Leila

AU - Hoeg-Jensen, Thomas

AU - Hoiberg-Nielsen, Rasmus

AU - Arleth, Lise

PY - 2020/8/3

Y1 - 2020/8/3

N2 - B29N(epsilon)-lithocholyl-gamma-L-beta Glu-desB30 human insulin [NN344] belongs to a group of insulins with fatty acid or sterol modifications. These insulin analogues have been found to form subcutaneous depots upon injection and hereby have a protracted release profile in vivo. In the present study, B29N(epsilon)-lithocholyl-gamma-L-Glu-desB30 human insulin was investigated using in-solution small-angle X-ray scattering (SAXS) at chemical conditions designed to mimic three stages during treatment in vivo: in-vial/pen, postinjection, and longer times after injection. We found that the specific insulin analogue formed a mixture of mono- and dihexamers under in-vial/pen conditions of low salt and stabilizing phenol. At postinjection, conditions mimicking a subcutaneous depot, B29N(epsilon)-lithocholyl-gamma-L-Glu-desB30 human insulin, formed very long straight soluble hexamer-based rods stacked along the Zn(II)-axis. The self-assembly was triggered by an increase in salt concentration when going from vial to physiological conditions. Mimicking longer times after injection and the additional removal of phenol caused the length of the rods to decrease significantly. Finally, we found that the self-assembly could be controlled by varying the amount of modification at the interaction interface by making mixed hexamers of B29N(epsilon)-lithocholyl-gamma-L-Glu-desB30 and desB30 human insulin. This opens extra possibilities for controlling the release profile of very-long-acting insulins.

AB - B29N(epsilon)-lithocholyl-gamma-L-beta Glu-desB30 human insulin [NN344] belongs to a group of insulins with fatty acid or sterol modifications. These insulin analogues have been found to form subcutaneous depots upon injection and hereby have a protracted release profile in vivo. In the present study, B29N(epsilon)-lithocholyl-gamma-L-Glu-desB30 human insulin was investigated using in-solution small-angle X-ray scattering (SAXS) at chemical conditions designed to mimic three stages during treatment in vivo: in-vial/pen, postinjection, and longer times after injection. We found that the specific insulin analogue formed a mixture of mono- and dihexamers under in-vial/pen conditions of low salt and stabilizing phenol. At postinjection, conditions mimicking a subcutaneous depot, B29N(epsilon)-lithocholyl-gamma-L-Glu-desB30 human insulin, formed very long straight soluble hexamer-based rods stacked along the Zn(II)-axis. The self-assembly was triggered by an increase in salt concentration when going from vial to physiological conditions. Mimicking longer times after injection and the additional removal of phenol caused the length of the rods to decrease significantly. Finally, we found that the self-assembly could be controlled by varying the amount of modification at the interaction interface by making mixed hexamers of B29N(epsilon)-lithocholyl-gamma-L-Glu-desB30 and desB30 human insulin. This opens extra possibilities for controlling the release profile of very-long-acting insulins.

KW - insulin

KW - SAXS

KW - self-assembly

KW - oligomer

KW - prolonged action

KW - ZINC-BINDING DOMAINS

KW - MONOMERIC INSULINS

KW - MECHANISM

KW - PROTRACTION

KW - DEGLUDEC

KW - DETEMIR

U2 - 10.1021/acs.molpharmaceut.0c00112

DO - 10.1021/acs.molpharmaceut.0c00112

M3 - Journal article

C2 - 32579369

VL - 17

SP - 2809

EP - 2820

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 8

ER -

ID: 247494397