Neurotrophins are a family of growth factors consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin-4/5 (NT-4/5). They exert their effects as homodimers, via the pan-neurotrophic receptor p75NTR, and/or their respective tropomyosin-kinase related (Trk) receptor. Often, they are biased toward one receptor on a specific cell type, resulting in vastly different effects. For example, BDNF has a pro-myelinating effect in the peripheral nervous system (PNS) via the p75NTR receptor. However, in the central nervous system (CNS), BDNF elicits a comparable effect via its corresponding Trk receptor: TrkB.1
The effects of BDNF are mediated by distinct ‘loop regions’ of the BDNF homodimer interacting with the receptors. These multiple-receptor actions of BDNF, along with its unfavourable pharmacokinetic properties, have made the protein a poor candidate for therapeutic applications. Our lab is particularly interested in understanding BDNF's ability to regulate remyelination in the PNS and CNS. To overcome the receptor promiscuity of BDNF, we have developed peptide structural mimetics of different loop-regions of BDNF, which are able to be produced in greater yields than the parent neurotrophin, are proteolytically stable, and most importantly are selective for a single receptor sub-type. We have also been able to demonstrate their ability to promote the regrowth of myelin in vitro and in vivo.2
This presentation will outline the design, development and analysis (in vitro and in vivo) of these peptide mimetics as potential therapeutic leads, but more immediately as chemical biology tools to study central and peripheral demyelinating diseases.
1. Molecular & Cellular Biology (2014) 63; 132-140
2. eNeuro (2017), 4 (3); 142-17