Editorial [ Targeting Neurotrophic Factors, Their Receptors, and Signalling Pathways with Small Molecule Mimetics and Modulators to Achieve Neuroprotection and Regeneration Guest Editor: Stephen D. Skaper ]

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. In spite of such encouraging experimental findings, clinical studies have proven largely disappointing. Although these proteins are natural products, they cannot be given orally, present uncertain pharmacokinetic behaviour, and large-scale production is labour and cost-intensive. For CNS diseases, 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. A detailed understanding of neurotrophic factor-receptor structure and interactions and intracellular signalling has been crucial in the design of peptidyl and non-peptidyl small molecule neurotrophin mimetics which interact directly with the receptor, or which potentiate neurotrophin activation of its cognate receptor. Another example of how such knowledge has been exploited is that of the low-affinity pan-neurotrophin receptor p75NTR, which can promote cell survival in the absence of Trk receptors. A pharmacophore designed to capture selected structural and physico-chemical features of a neurotrophin domain known to interact with p75NTR was applied to in silico screening of small molecule libraries to select neurotrophic compounds. Other strategies include intracellular effector-targeting approaches, which capitalise on knowledge of signalling pathways involved in neuronal cell survival and demise, and which can be agonised or antagonised to promote neuroprotection. This issue will begin with a brief overview on the biology neurotrophic proteins, followed by articles describing strategies taken towards the development of small molecule mimetics for neurotrophic factors and the emerging drug candidates, and will encompass both receptor-directed as well as intracellular signalling approaches. Moreover, exciting recent data describing G-protein-coupled receptor transactivation of Trk receptors and their downstream signalling pathways raise the possibility of using small molecule G-protein-coupled receptor ligands as a new strategy for promoting trophic effects during neurodegeneration. While many challenges lie ahead, the development of neurotrophic compounds is potentially very rewarding and appears to offer real promise for disease modification. Neurotrophic drug development, however, has historically been a high-risk approach. Nonetheless, novel emerging targets and technological improvements, as well as the development of biomarkers that can act as surrogates to assess drug activity at the defined molecular target together with a more focused effort on translational medicine approaches may facilitate the development of neurotrophic small molecules with lower associated attrition rates.