Development of Peptide NGF Agonists. Nerve growth factor (NGF) is a polypeptide involved in the development and maintenance of the nervous system, affecting cells of the peripheral sympathetic nervous system as well as central cholinergic neuronal survival and neurite outgrowth. NGF belongs to a superfamily of neurotrophic molecules which have similar effects on other neuronal populations. For penetrating the central nervous system, peptides are generally preferable to large polypeptides. There has been considerable interest in development of peptide NGF agonists for the therapy of Alzheimer's disease, post-stroke and trauma, and recently such peptides have been demonstrated. This group has designed and tested peptide agonists in in vitro models. The crystal structure and extensive (1) structure-function data for NGF are available. The resources of the Computer Graphics Laboratory are being used to explore the structure of NGF and NGF dimers and, where possible, model NGF peptides and their multimeric forms, with the aims of better understanding NGF-receptor interactions and creating more effective agonists. Interleukin-beta Converting Enzyme (ICE) Analogues and Inhibitors. Members of the ICE family have been implicated in programmed cell death. The crystal structure of ICE has been determined, but ICE itself is involved in only a restricted population of cells with multiple other family members active elsewhere. CGL resources (e.g. LOOK) are being used to compare active site regions of ICE with other family members and model inhibitory peptides with the aim of designing more effective and selective inhibitors.
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