Tandem Repeat Peptide Strategy for the Design of Neurotrophic Factor Mimetics

Gareth      Williams; Gareth      Williams; Francisco      Molina-Holgado; Francisco      Molina-Holgado; Patrick      Doherty; Patrick      Doherty

Abstract

Neurotrophic factors comprise a broad family of secreted proteins that have growth promoting, survival promoting and differentiation inducing activities. Disruption of neurotrophic factor signalling is a characteristic of many central and peripheral nervous system disorders, such as Alzheimers disease, Parkinsons disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and peripheral neuropathy and pain. It follows that treating patients with neurotrophic factors might be beneficial in a range of neurological diseases. However, the promising results seen in animal models of disease have not translated well into clinical trials due to the poor pharmacokinetics associated with the intact proteins, in particular, their short in vivo half-life, low blood brain barrier permeability, limited diffusion, and undesirable effects through multiple receptor interactions. This has been the main motivation for the design of small molecule modulators of the neurotrophic factor pathways. The review gives a brief survey of the various strategies to design mimetics that have been reported in the literature with special emphasis on the tandem repeat peptide agonist approach for BDNF/NT-4/5 and N-cadherin mimetics.

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