Abstract
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of neurotrophic factors. BDNF has long been recognized to have potential for the treatment of a variety of human neurodegenerative diseases. However, clinical trials with recombinant BDNF have yet to yield success, leading to the suggestion that alternative means of harnessing BDNF actions for therapeutic use may be required. Here we describe an approach to create low molecular weight peptides that, like BDNF, promote neuronal survival. The peptides were designed to mimic a cationic tripeptide sequence in loop 4 of BDNF shown in previous studies to contribute to the binding of BDNF to the common neurotrophin receptor p75NTR. The best of these peptides, the cyclic pentapeptide 2 (cyclo(-D-Pro-Ala-Lys-Arg-)), despite being of low molecular weight (Mr 580), was found to be an effective promoter of the survival of embryonic chick dorsal root ganglion sensory neurons in vitro (maximal survival, 68 +/- 3% of neurons supported by BDNF). Pentapeptide 2 did not affect the phosphorylation of either TrkB (the receptor tyrosine kinase for BDNF) or the downstream signaling molecule MAPK, indicating that its mechanism of neuronal survival action is independent of TrkB. NMR studies reveal that pentapeptide 2 adopts a well defined backbone conformation in solution. Furthermore, pentapeptide 2 was found to be effectively resistant to proteolysis when incubated in a solution of rat plasma in vitro. These properties of pentapeptide 2 (low molecular weight, appropriate pharmacological actions, a well defined solution conformation, and proteolytic stability) render it worthy of further investigation, either as a template for the further design of neuronal survival promoting agents or as a lead compound with therapeutic potential in its own right.
Highlights
The effects of Brain-derived neurotrophic factor (BDNF) and the other neurotrophins are produced via two transmembrane receptors: members of the Trk family of receptor tyrosine kinases, and the glycoprotein p75NTR
Cyclic peptides incorporating a variety of conformational constraints were designed, and selected compounds were synthesized and examined for (i) their ability to promote the survival of cultures of embryonic chick sensory neurons, (ii) their ability to affect signaling through the receptors for BDNF, and (iii) their susceptibility to proteolytic degradation in rat plasma in vitro
We have used a structure-based design approach to develop small monomeric circular peptides aimed at mimicking the putative p75NTR-binding cationic tripeptide sequence within loop 4 of BDNF
Summary
Neurotrophins exist as homodimers of ϳ2 ϫ 120 residues. Numerous x-ray crystal structures (e.g. see Refs. 13–15) demonstrate that the neurotrophins adopt a common three-dimensional fold, with each monomer consisting of seven longtitudinal -strands connected by three solvent-exposed hairpin loops (loops 1, 2, and 4) and a longer loop (loop 3). Further examinations with disulfide-constrained cyclic peptides based on loops 1 and 4 of BDNF revealed that generally, monomeric, monocyclic peptides as well as heterodimeric bicyclic peptides are BDNF inhibitors, whereas homodimeric, bicyclic peptides are BDNF-like agonists [24] They are significantly reduced in size compared with BDNF itself, the molecular weight and complex nature of these dimeric peptides would pose considerable challenges for their development as clinically useful agents. Cyclic peptides incorporating a variety of conformational constraints were designed, and selected compounds were synthesized and examined for (i) their ability to promote the survival of cultures of embryonic chick sensory neurons, (ii) their ability to affect signaling through the receptors for BDNF, and (iii) their susceptibility to proteolytic degradation in rat plasma in vitro. Two-dimensional NMR spectroscopy methods were used to determine the three-dimensional structure of one of these circular peptides in solution
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