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The identification of inhibitors of nerve growth factor and brain-derived neurotrophic factor

The identification of inhibitors of nerve growth factor and brain-derived neurotrophic factor
The identification of inhibitors of nerve growth factor and brain-derived neurotrophic factor
Chronic pain affects up to 43% of the UK population, with 12% reporting moderate to severely limiting chronic pain.1-2 This incidence rate rises with age, with 62% of over 75s being diagnosed.1 The current standard of care for chronic pain almost exclusively involves COX-1, COX-2 or μ-opioid receptor inhibitors and considerable research has been conducted in this area. Despite this, the current state of pharmacological treatments is seen by patients as decidedly lacking, with the prevailing opinion being one of concern for efficacy, side effects and addiction.

Recent drug advances suggest a promising new area for development may be found in inhibiting neurotrophins or their receptors: both animal modelling and clinical trials show that significant reduction of pain sensation (nociception) may be found in the inhibition of these proteins. This is supported by Pfizer’s Tanezumab, which recently (June 2017) received FDA fast-track approval status for the treatment of chronic pain in patients with osteoarthritis and chronic lower back pain. This monoclonal antibody binds to nerve growth factor (βNGF) to prevent it binding to its receptor, and has been shown to dramatically reduce nociception. Despite this, Tanezumab shows room for improvement: a meta-analysis of trials involving Tanezumab for treatment of osteoarthritis of the knee revealed significant discontinuations due to adverse effects.3 A Phase III trial for osteoarthritic hip pain (while successful) also showed an increase in the required number of hip replacements for those taking the drug.4 Further development is therefore sought, and this research documents the initial hit discovery and development of a number of neurotrophin inhibitors.

Initially this was sought through the development of a high throughput screening platform using a reverse two-hybrid system, however this proved unsuccessful. Phage display was therefore employed and successfully identified a number of peptides which bound to either βNGF or another promising neurotrophin target, mBDNF. This adherence was then tested for its target specificity, and an ELISA screen developed to assess agonist/antagonist activity. Peptides were then synthesised and further assays were attempted to ascertain binding data. Finally, the biological activity of the lead peptides was tested against TrkB/PC12 cells in western blot and morphology assays.

In conclusion, this research identified several antagonists and antagonists of the neurotrophin-receptor interaction for βNGF and mBDNF.
University of Southampton
Ingram, James David
2d63d67f-3ce9-4429-b679-2408170f6d54
Ingram, James David
2d63d67f-3ce9-4429-b679-2408170f6d54
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2

Ingram, James David (2017) The identification of inhibitors of nerve growth factor and brain-derived neurotrophic factor. University of Southampton, Doctoral Thesis, 265pp.

Record type: Thesis (Doctoral)

Abstract

Chronic pain affects up to 43% of the UK population, with 12% reporting moderate to severely limiting chronic pain.1-2 This incidence rate rises with age, with 62% of over 75s being diagnosed.1 The current standard of care for chronic pain almost exclusively involves COX-1, COX-2 or μ-opioid receptor inhibitors and considerable research has been conducted in this area. Despite this, the current state of pharmacological treatments is seen by patients as decidedly lacking, with the prevailing opinion being one of concern for efficacy, side effects and addiction.

Recent drug advances suggest a promising new area for development may be found in inhibiting neurotrophins or their receptors: both animal modelling and clinical trials show that significant reduction of pain sensation (nociception) may be found in the inhibition of these proteins. This is supported by Pfizer’s Tanezumab, which recently (June 2017) received FDA fast-track approval status for the treatment of chronic pain in patients with osteoarthritis and chronic lower back pain. This monoclonal antibody binds to nerve growth factor (βNGF) to prevent it binding to its receptor, and has been shown to dramatically reduce nociception. Despite this, Tanezumab shows room for improvement: a meta-analysis of trials involving Tanezumab for treatment of osteoarthritis of the knee revealed significant discontinuations due to adverse effects.3 A Phase III trial for osteoarthritic hip pain (while successful) also showed an increase in the required number of hip replacements for those taking the drug.4 Further development is therefore sought, and this research documents the initial hit discovery and development of a number of neurotrophin inhibitors.

Initially this was sought through the development of a high throughput screening platform using a reverse two-hybrid system, however this proved unsuccessful. Phage display was therefore employed and successfully identified a number of peptides which bound to either βNGF or another promising neurotrophin target, mBDNF. This adherence was then tested for its target specificity, and an ELISA screen developed to assess agonist/antagonist activity. Peptides were then synthesised and further assays were attempted to ascertain binding data. Finally, the biological activity of the lead peptides was tested against TrkB/PC12 cells in western blot and morphology assays.

In conclusion, this research identified several antagonists and antagonists of the neurotrophin-receptor interaction for βNGF and mBDNF.

Text
18.03.25 J. Ingram - Thesis - Final - Version of Record
Restricted to Repository staff only until 28 June 2021.
Available under License University of Southampton Thesis Licence.

More information

Published date: September 2017

Identifiers

Local EPrints ID: 422241
URI: http://eprints.soton.ac.uk/id/eprint/422241
PURE UUID: 57475465-032c-4e82-bc7a-56df5aa9d976
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

Catalogue record

Date deposited: 19 Jul 2018 16:30
Last modified: 14 Mar 2019 01:41

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