Self-assembled peptide as a long-acting drug formulation
Welland, Mark E.
University of Cambridge
Doctor of Philosophy (PhD)
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Kinna, S. (2019). Self-assembled peptide as a long-acting drug formulation (Doctoral thesis). https://doi.org/10.17863/CAM.49171
Type 2 Diabetes Mellitus (T2DM) and obesity are widespread and associated metabolic diseases with worldwide rising prevalence . The gut hormone Oxyntomodulin induces satiety and normalizes hyperglycaemia without risk of hypoglycaemic excursions . However, native incretin hormones are quickly degraded by peptidases and renally excreted, which has so far impaired pharmaceutical exploitation of anorectic and glucose-homeostatic activities . It is known that many – if not all – peptides can be converted to self-assembled nanostructures . Amyloid fibrils are characterized by enhanced chemical, biological and mechanic stability compared to soluble peptides, and allow a controlled release by dissociation of monomers from the fibril termini . Here I propose self-assembled peptides as a prolonged-activity, self-mediated drug delivery system for subcutaneous injection of pharmaceutically active drugs. Oxyntomodulin is used as a model peptide due to previously futile attempts at finding long-acting analogues, and Oxyntomodulin’s so far unreported self-assembly behaviour. This thesis shows a method to reproducibly form subcutaneously injectable Oxyntomodulin fibrils with high conversion yield and low polydispersity, as well as methods to characterize morphology, kinetics and thermodynamics of Oxyntomodulin self-assembly. Oxyntomodulin fibrils display amyloid-like characteristics and release soluble peptide in a peptide-deprived environment. Association and dissociation kinetics and thermodynamics are sensitively dependent on salts and temperature, with an association temperature optimum at room temperature that is unique in amyloid-type self-assembly. An alternative fibril type forms under different conditions and displays altered fibrillation kinetics and thermodynamics. The specificity of fibrillation to the peptide sequence is shown in presence of Oxyntomodulin’s sister peptide glucagon and the analogue Aib-2-Oxyntomodulin. Extended release of active peptide from a subcutaneous Oxyntomodulin fibril depot has been proved in rodent studies at MedImmune . As amyloid-like self-assembly is a generic feature of the peptide chain, the strategies and methods described in this project can be applied to other pharmaceutically active peptides and proteins.
peptide, self-assembly, type 2 diabetes, obesity, oxyntomodulin, glucagon, amyloid, QDM-D, Cryo-EM, AFM, fibrillation, kinetics, thermodynamics
This project was fully funded by MedImmune, LLC under grant number RG77937.
This record's DOI: https://doi.org/10.17863/CAM.49171
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