Design of a Conformationally Defined and Proteolytically Stable Circular Mimetic of Brain-derived Neurotrophic Factor

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 p75 NTR . The best of these peptides, the cyclic pentapeptide 2 (cyclo(-D-Pro-Ala-Lys-Arg-)), despite being of low molecular weight (M r 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. BDNF5 is a member of the neurotrophin family of neurotrophic factors, along with nerve growth factor (NGF), neurotrophin (NT)-3 and NT-4/5 (1). These proteins play a key role in shaping the vertebrate nervous system during embryonic development by regulating naturally occurring neuronal death (2). They have also long been touted as having potential for the treatment for human neurodegenerative diseases, due to their neurotrophic effects on specific neuronal populations that are lost in these diseases. BDNF is particularly attractive in this respect, since it has been shown to promote the survival and/or prevent the degeneration of motor neurons (involved in amyotrophic lateral sclerosis) (3), populations of sensory neurons (sensory neuropathies) (4), basal forebrain cholinergic neurons (Alzheimer disease) (5), and dopaminergic neurons of the substantia nigra (Parkinson disease) (6). More recently, it has been demonstrated that BDNF probably plays a specific role in the etiology of Huntington disease, indicating an exciting potential for therapies aimed at replacing BDNF or otherwise mimicking its actions in this condition (7).The effects of BDNF and the other neurotrophins are produced via two transmembrane rec...

Brain-Derived Neurotrophic Factor and Neuropsychiatric Disorders

“…BDNF "mimetic" peptides have been developed in the last several years (Yang et al, 2005;Fletcher et al, 2008;Jang et al, 2010). Preclinical studies have yet to fully characterize these BDNF mimetic peptides, but recent evidence suggests that 7,8-dihydroxyflavone may enhance fear-conditioned memory in rodents (Andero et al, 2011).…”

Cyclo-prolylalanine: the neuroprotective and antioxidative properties on the model of acute cerebral disease in rats

“…Пред-полагается его влияние на ряд патогенетических звеньев ишемического каскада, например, умень-шение токсичности N-метил-D-аспартата или про-дукции провоспалительных цитокинов. Из работы [24] известен другой пентапептид, гомологичный аминокислотным участкам 1-2 дипептиду DKP-9 -cyclo(d-Pro-ala-Lys-Arg), синтезированный на ос-нове изгиба 4-й петли нейротрофического фактора мозга (BDNF [94][95][96] ). В экспериментах in vitro показана его способность повышать выживаемость чувстви-тельных нейронов спинальных ганглиев, реализу-ющаяся путем, отличным от нейропротекторного действия BDNF или фактора роста нервов (NGF).…”

Selectivity of Cell Signaling in the Neuronal Response Based on NGF Mutations and Peptidomimetics in the Treatment of Alzheimers Disease

“…Good NGF mimetics at this stage appear to be D3 or its derivatives and LM11A-24 or LM11A-31, although each may potentially be useful for a distinct purpose. Also being developed are TrkB (O' Leary & Hughes, 2003;Fletcher, et al, 2008;Fletcher & Hughes, 2009) and TrkC Chen, et al, 2009;Liu, et al, 2010) antagonists/agonists. BDNF mimetics have made progress toward a useful therapeutic reagent with efficacy studies in rodents (Massa et al, 2010).…”