NT 4/5: Tandem repeat Peptide strategy for the design of neurotrophic factor mim

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CNS Neurol Disord Drug Targets. 2008 Feb;7(1):110-9.

Tandem repeat Peptide strategy for the design of neurotrophic factor

mimetics.Molina-Holgado F, Doherty P, G.

Wolfson Centre for Age-Related Diseases, King's College London,

London SE1 1UL, UK.

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 Alzheimer's disease, Parkinson's 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.