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Self-Assembly of Exendin-4-Derived Dual Peptide Agonists is Mediated by Acylation and Correlated to the Length of Conjugated Fatty Acyl Chains
- Publication Year :
- 2020
-
Abstract
- Dual glucagon-like peptide-1/glucagon receptor agonists have emerged as promising candidates for the treatment of diabetes and obesity. Issues of degradation sensitivity and rapid renal clearance are addressed, for example, by the conjugation of peptides to fatty acid chains, promoting reversible albumin binding. We use combined dynamic and static light scattering to directly measure the self-assembly of a set of dual peptide agonists based on the exendin-4 structure with varying fatty acid chain lengths in terms of apparent molecular mass and hydrodynamic radius (R-S). We use NMR spectroscopy to gain an insight into the molecular architecture of the assembly. We investigate conformational changes of the monomeric subunits resulting from peptide self-assembly and assembly stability as a function of the fatty acid chain length using circular dichroism and fluorescence spectroscopy. Our results demonstrate that self-assembly of the exendin-4-derived dual agonist peptides is essentially driven by hydrophobic interactions involving the conjugated acyl chains. The fatty acid chain length affects assembly equilibria and the assembly stability, although the peptide subunits in the assembly retain a dynamic secondary structure. The assembly architecture is characterized by juxtaposition of the fatty acyl side chains and a hydrophobic cluster of the peptide moiety. This cluster experiences local conformational changes in the assembly compared to the monomeric unit leading to a reduction in solvent exposure. The N-terminal half of the peptide and a C-terminal loop are not in contact with neighboring peptide subunits in the assemblies. Altogether, our study contributes to a thorough understanding of the association characteristics and the tendency toward self-assembly in response to lipidation. This is important not only to achieve the desired bioavailability but also with respect to the physical stability of peptide solutions.
- Subjects :
- Circular dichroism
Magnetic Resonance Spectroscopy
Acylation
Pharmaceutical Science
Lipid-anchored protein
Peptide
02 engineering and technology
030226 pharmacology & pharmacy
Glucagon-Like Peptide-1 Receptor
Protein Structure, Secondary
Hydrophobic effect
03 medical and health sciences
0302 clinical medicine
Glucagon-Like Peptide 1
ddc:570
Drug Discovery
Side chain
Receptors, Glucagon
Animals
Amino Acid Sequence
Protein secondary structure
Institut für Biochemie und Biologie
chemistry.chemical_classification
Circular Dichroism
Fatty acid
Lizards
021001 nanoscience & nanotechnology
Fatty Acids, Volatile
Dynamic Light Scattering
Molecular Weight
chemistry
ddc:540
Biophysics
Molecular Medicine
Exenatide
0210 nano-technology
Hydrophobic and Hydrophilic Interactions
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....b509c9c2688b5820336fba7b7e4ec86f