Novel monocyclic and bicyclic loop mimetics of brain-derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF) is a protein that promotes the survival of neurons. It is widely thought to possess clinical potential for the treatment of neurodegenerative diseases, and in recent years, has been found to play a role in the pathogenesis of some tumours. BDNF is thought to bind to its cellular receptors trkB and p75(NTR) primarily by way of solvent-exposed loops on the BDNF dimer. In this paper, we describe our recent progress towards the development of small peptides as mimetics and inhibitors of BDNF. Two classes of peptides were prepared: disulphide-constrained monomeric monocyclic peptides designed to mimic a single solvent-exposed loop; and homo- and heterodimeric bicyclic peptides designed to mimic pairs of loops. Each peptide was examined in cultures of embryonic chick dorsal root ganglion sensory neurons, both alone, and in competition with BDNF. All peptides were found to inhibit BDNF-mediated neuronal survival, while one--a dimeric peptide based on the two loop 4 regions of BDNF--behaved as a partial BDNF-like agonist. The work described in this paper supports the proposed receptor-binding role of loops 1, 2, and 4 of BDNF, and provides valuable steps towards our long-term goal of developing BDNF mimetics and inhibitors for clinical use.