Towards an Understanding of the Role of VGF-Derived Peptides

Ashford, Toni Winona Marie (2021) Towards an Understanding of the Role of VGF-Derived Peptides. MRes thesis, University of Nottingham.

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Abstract

Pro-VGF, a product of the vgf gene, is expressed in abundance in neuronal and neuroendocrine cells, including the β cells of the islet of Langerhans. Post translational endoproteolytic processing of pro-VGF results in formation of several biologically active peptides, which are secreted in response to different stimuli and have been shown to have various physiological roles including glycaemic control, memory and learning.

The aim of this project was to synthesise VGF-derived peptides to assess biological function, particularly in relation to diabetes mellitus and neurodegenerative diseases. Evidence suggests that VGF-derived peptides could function as tissue-specific regulators of glucose homeostasis. It has been hypothesised that the VGF-derived peptide TLQP-62 functions as an insulin secretagogue via direct interaction with pancreatic islet β cells. However, a receptor is yet to be identified and further understanding of the role of this peptide in glucose homeostasis is required. Further insight into which tissue(s) TLQP-62 interacts with, ultimately leading to receptor identification, would be highly impactful. Furthermore, half-life data indicating whether TLQP-62 reaches the tissue(s) in a pharmacologically active concentration would infer whether longer acting analogues are required. Synthesis of TLQP-62 via solid phase peptide synthesis and a rapid and additive-free peptide ligation technique, termed “diselenide-selenoester ligation,” followed by phosphinemediated deselenisation has successfully been carried out.

Localised change in VGF-derived peptide levels has been attributed to several neurodegenerative diseases, for example Amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease and frontotemporal dementia. VGF-derived peptides AQEE-30 and GGEE45 have been shown to be decreased in the cerebrospinal fluid of patients affected with Alzheimer’s disease. Furthermore, altered expression of AQEE-30 has been observed in the parietal cortex. Synthesis of AQEE-30 and GGEE-8 (a truncated version of GGEE-45) has been successfully achieved using solid phase peptide synthesis.

The aim is that, in the future, which tissue(s) TLQP-62 interacts with and whether longer acting analogues are required will be determined, using N-terminal fluorine as a radionuclide. Furthermore, the biological function of AQEE-30 and GGEE-8 will be evaluated in the future by Dr Preeti Jethwa using Drosophila melanogaster flies.

Item Type: Thesis (University of Nottingham only) (MRes)
Supervisors: Mitchell, Nicholas J.
Jethwa, Preeti
Keywords: peptide synthesis, therapeutics, homeostasis
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry > QD415 Biochemistry
Q Science > QP Physiology > QP501 Animal biochemistry
R Medicine > RM Therapeutics. Pharmacology
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 65070
Depositing User: Ashford, Toni
Date Deposited: 04 Aug 2021 04:41
Last Modified: 04 Aug 2021 04:41
URI: http://eprints.nottingham.ac.uk/id/eprint/65070

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