Design of a conformationally defined and proteolytically stable circular mimetic of brain-derived neurotrophic factor.
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.
Fletcher
Jordan M
JM
Department of Pharmacology, University of Melbourne, Victoria 3010, Australia.
Morton
Craig J
CJ
Zwar
Richard A
RA
Murray
Simon S
SS
O'Leary
Paul D
PD
Hughes
Richard A
RA
D000818:Animals; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D006801:Humans; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D009842:Oligopeptides; D020800:Receptor, Nerve Growth Factor; D020813:Receptor, trkB; D048049:Extracellular Signal-Regulated MAP Kinases