Peptide Mimetics of Neurotrophins and their Receptors

S.      D. Skaper

Abstract

Neurotrophic factors were originally identified based on their ability to prevent naturally occurring cell death in the developing nervous system. Many of these proteins also promote survival after injury or protect neurons in toxin-disease models in animals. In addition to neuroprotective effects, these factors exert trophic effects on neurons, stimulating increases in neuronal metabolism, cell size, and process outgrowth. These properties underlie expectations for neurorestoration, in which growth of new axons and synapses could lead to functional improvement, which is of great interest for those patients who are already significantly disabled by disease. Preclinical and clinical data suggest that subcutaneous or intravenous administration of neurotrophic factors may be effective for the treatment of peripheral nervous system diseases. However, even though these proteins are natural products, they do present specific problems when used as therapeutic agents. They cannot be given orally, present uncertain pharmacokinetic behavior, and large-scale production is labor and costintensive. Neurotrophic factor treatment of central nervous system diseases presents an even more complex scenario, since they are not able to cross the blood-brain barrier and must be given intracerebrally. Although there is an active search for alternative delivery strategies, for central nervous system diseases in particular the advantages of small molecule mimetics over proteins are evident. Small organic molecules can be modified to penetrate freely into the brain parenchyma and can be designed for oral administration. There are several possible approaches for replacing neurotrophic proteins with small molecule mimetics. For therapeutic use in the peripheral nervous system, neurotrophic proteins could be replaced by active peptide fragments with receptor binding properties similar to the full-length protein, but improved pharmacokinetic properties and lower production costs. In principle, it should be possible to replace the entire protein or fully active peptide fragment by a non-peptidic molecule binding to the same receptor site. It may be possible to regulate neurotrophic factor receptor activity by allosterically-acting molecules which influence the functional efficacy of the receptors. Other strategies include intracellular effector-targeting approaches, which are based on knowledge of signaling pathways involved in neuronal cell survival and demise, and which can be agonized or antagonized to promote neuroprotection. This chapter will begin with a brief overview on the biology neurotrophic proteins, followed with a description of strategies taken towards the development of small molecule mimetics for neurotrophic factors and the emerging drug candidates. The latter will encompass both receptor-directed as well as intracellular signalling approaches.

Keywords: Nerve growth factor, brain-derived growth factor, neurotrophin-3, neurotrophin - 4/5, glial cell line-derived neurotrophic factor, receptor tyrosine kinases, neuroprotection, neuroregeneration, Alzheimer's disease, monoclonal antibodies