Oligomerization of a Glucagon-like Peptide 1 Analog: Bridging Experiment and Simulations

Biophysical Journal
Tine M FrederiksenGünther H Peters

Abstract

The glucagon-like peptide 1 (GLP-1) analog, liraglutide, is a GLP-1 agonist and is used in the treatment of type-2 diabetes mellitus and obesity. From a pharmaceutical perspective, it is important to know the oligomerization state of liraglutide with respect to stability. Compared to GLP-1, liraglutide has an added fatty acid (FA) moiety that causes oligomerization of liraglutide as suggested by small-angle x-ray scattering (SAXS) and multiangle static light scattering (MALS) results. SAXS data suggested a global shape of a hollow elliptical cylinder of size hexa-, hepta-, or octamer, whereas MALS data indicate a hexamer. To elaborate further on the stability of these oligomers and the role of the FA chains, a series of molecular-dynamics simulations were carried out on 11 different hexa-, hepta-, and octameric systems. Our results indicate that interactions of the fatty acid chains contribute noticeably to the stabilization. The simulation results indicate that the heptamer with paired FA chains is the most stable oligomer when compared to the 10 other investigated structures. Theoretical SAXS curves extracted from the simulations qualitatively agree with the experimentally determined SAXS curves supporting the view that lirag...Continue Reading

References

May 25, 1977·Journal of Molecular Biology·F C BernsteinM Tasumi
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Feb 15, 2000·Regulatory Peptides·B GallwitzW E Schmidt
Jun 1, 2002·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Eric GrouzmannJean-Silvain Lacroix
Jun 26, 2003·Nucleic Acids Research·Elisabeth GasteigerAmos Bairoch
Aug 28, 2004·Diabetes·Carolyn F Deacon
Feb 20, 2007·Pharmacology & Therapeutics·Máire E Doyle, Josephine M Egan
Aug 29, 2007·Proceedings of the National Academy of Sciences of the United States of America·Hyeung-Jin JangJosephine M Egan
Dec 2, 2008·Molecular and Cellular Endocrinology·David Russell-Jones
Nov 26, 2010·Physical Chemistry Chemical Physics : PCCP·Antonio StoccoDominique Langevin
Jan 18, 2011·Experimental Cell Research·Bo Ahrén
May 13, 2011·The Journal of Physical Chemistry. B·Jesper J MadsenGünther H Peters
Feb 15, 2012·Advances in Nutrition·Sofia Moran-RamosNimbe Torres
Jun 6, 2012·Experimental Diabetes Research·Francis S Willard, Kyle W Sloop
Oct 2, 2012·Journal of Neurochemistry·Kalpana VelmuruganSubbiah Pugazhenthi
Jun 4, 2013·Drug Discovery Today·Allan A Kaspar, Janice M Reichert
Feb 18, 2014·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Konrad Talbot, Hoau-Yan Wang
Apr 4, 2014·European Journal of Internal Medicine·Asger LundTina Vilsbøll
Mar 28, 2012·Journal of Diabetes Investigation·Kenichi SakuraiTakashi Miki
Apr 30, 1998·The Journal of Physical Chemistry. B·A D MacKerellM Karplus
Jul 6, 2014·Diabetes/metabolism Research and Reviews·Hale M TasyurekSalih Sanlioglu
Apr 1, 2012·Journal of Applied Crystallography·Maxim V PetoukhovDmitri I Svergun
Jan 9, 2015·Molecular Pharmaceutics·Ying WangGeorge B Benedek
Apr 8, 2015·Drug Design, Development and Therapy·Ellen E Ladenheim

❮ Previous
Next ❯

Citations

Aug 9, 2016·Journal of Pharmaceutical Sciences·Suzanne M D'AddioAllen C Templeton
Jan 28, 2017·Journal of Peptide Science : an Official Publication of the European Peptide Society·J A HutchinsonI W Hamley
Feb 8, 2018·The Journal of Biological Chemistry·Angélique Gajahi SoudahomeJoël Couprie
Apr 6, 2019·Acta Crystallographica. Section D, Structural Biology·Line A RybergPernille Harris
Nov 16, 2018·Science Translational Medicine·Stephen T BuckleyLotte Bjerre Knudsen
Jul 16, 2019·Journal of Pharmaceutical Sciences·John S PhiloTsutomu Arakawa
Aug 31, 2017·Journal of Chemical Information and Modeling·Pernille SønderbyGünther H J Peters
Oct 30, 2021·Obesity Reviews : an Official Journal of the International Association for the Study of Obesity·Stefano Del PratoJuris J Meier

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cardiovascular Biology of GLP-1

Glucagon-like peptide 1 (GLP-1) plays a role in glucose metabolism, energy homeostasis, and inflammation suppression. GLP-1 receptor signaling has been shown to impact cardiovascular function. This feed focuses on the role of GLP-1 and GLP-1 receptor agonists on cardiovascular biology.

Related Papers

Nihon rinsho. Japanese journal of clinical medicine
T Matsuyama, Ryoya Komatsu
Nihon rinsho. Japanese journal of clinical medicine
Tatsuo Matsuyama
Nihon rinsho. Japanese journal of clinical medicine
Tatsuo Matsuyama, Ryoya Komatsu
© 2021 Meta ULC. All rights reserved