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    Thermo-Responsive self-assembly of a dual glucagon-like peptide and glucagon receptor agonist

    Year: 2021

    Journal: Int. J. Pharm., Volume 604, JUL 15

    Authors: Kinna, Sonja; Ouberai, Myriam M.; Sonzini, Silvia; Dos Santos, Ana L. Gomes; Welland, Mark E.

    Organizations: AstraZeneca [RG77937]

    Keywords: Self-assembly; Depot formulation; Oxyntomodulin; GLP-1; Glucagon

    The human peptide hormone Oxyntomodulin (Oxm) is known to induce satiety, increase energy expenditure, and control blood glucose in humans, making it a promising candidate for treatment of obesity and/or type 2 diabetes mellitus. However, a pharmaceutical exploitation has thus far been impeded by fast in vivo clearance and the molecule's sensitivity to half-life extending structural modifications. We recently showed that Oxm self-assembles into amyloid-like nanofibrils that continuously release active, soluble Oxm in a peptide-deprived environment. S.c. injected Oxm nanofibrils extended plasma exposure from a few hours to five days in rodents, compared to s.c. applied soluble Oxm. Here we show that Oxm fibril elongation kinetics and thermodynamics display a uniquely low temperature optimum compared to previously reported amyloid-like peptide and protein assemblies. Elongation rate is optimal at room temperature, with association rates 2-3 times higher at 25 degrees C than at >= 37 degrees C or <= 20 degrees C. We deduce from a combination of Cryo electron microscopy and spectroscopic methods that Oxm fibrils have a double-layered, triangular cross-section composed of arch-shaped monomers. We suggest a thermodynamic model that links the necessary molecular rearrangements during fibrillation and peptide release to the unique temperature effects in Oxm self-assembly and disassembly.
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