Modified low molecular weight cyclic peptides as mimetics of BDNF with improved potency, proteolytic stability and transmembrane passage in vitro

Fletcher, Jordan M.; Hughes, Richard A.

doi:10.1016/j.bmc.2009.02.053

Cited by 36 publications

(27 citation statements)

References 37 publications

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“…So far, a few small peptides and compounds have been reported to activate the TrkB receptor and might act as TrkB agonists [24, 25]. Nonetheless, these molecules do not fully imitate BDNF or regulate TrkB physiological functions in animals.…”

Section: Discussionmentioning

confidence: 99%

O-Methylated Metabolite of 7,8-Dihydroxyflavone Activates TrkB Receptor and Displays Antidepressant Activity

Liu¹,

Qi²,

Xiao³

et al. 2013

Pharmacology

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7,8-Dihydroxyflavone (7,8-DHF) acts as a TrkB receptor-specific agonist. It mimics the physiological actions of brain-derived neurotrophic factor (BDNF) and demonstrates remarkable therapeutic efficacy in animal models of various neurological diseases. Nonetheless, its in vivo pharmacokinetic profiles and metabolism remain unclear. Here we report that 7,8-DHF and its O-methylated metabolites distribute in mouse brain after oral administration. Both hydroxy groups can be mono-methylated, and the mono-methylated metabolites activate TrkB in vitro and in vivo. Blocking methylation, using COMT inhibitors, diminishes the agonistic effect of TrkB activation by 7,8-DHF or 4′-dimethylamino-7,8-DHF, supporting the contribution of the methylated metabolite to TrkB activation in mouse brain. Moreover, we have synthesized several methylated metabolite derivatives, and they also potently activate the TrkB receptor and reduce immobility in both forced swim test and tail suspension test, indicating that these methylated metabolites may possess antidepressant activity. Hence, our data demonstrate that 7,8-DHF is orally bioavailable and can penetrate the brain-blood barrier. The O-methylated metabolites are implicated in TrkB receptor activation in the brain.

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Section: Discussionmentioning

confidence: 99%

O-Methylated Metabolite of 7,8-Dihydroxyflavone Activates TrkB Receptor and Displays Antidepressant Activity

Liu¹,

Qi²,

Xiao³

et al. 2013

Pharmacology

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“…Having shown that TDP6 promoted oligodendrocyte myelination, we next aimed to verify whether this was achieved via targeting TrkB. To do this, we first used cyclo-DPAKKR, a monomeric mimetic of the loop 4 region of BDNF that acts as a putative p75 NTR agonist (Fletcher et al, 2008;Fletcher and Hughes, 2009). We have recently shown that cyclo-DPAKKR promotes Schwann cell myelination in vitro and in vivo, an effect dependent on neuronal p75 NTR expression .…”

Section: Cyclo-dpakkr Failed To Promote Myelination By Oligodendrocytesmentioning

confidence: 98%

“…We have previously described a 3D structurebased design approach that has yielded several classes of small peptides that mimic solvent exposed loops 2 and 4 of BDNF, the regions involved in binding to TrkB and p75 NTR respectively. Using this approach, we have developed cyclo-DPAKKR (Table 1), a monomeric mimetic of loop 4 that act as putative p75NTR agonist (Fletcher et al, 2008;Fletcher and Hughes, 2009;Xiao et al, 2013); and tricyclic dimeric peptide 6 (TDP6) (Table 1), a dimeric mimetic of loop 2 that acts as a putative TrkB agonist (O'Leary and Hughes, 2003).…”

Section: Introductionmentioning

confidence: 99%

TDP6, a brain-derived neurotrophic factor-based trkB peptide mimetic, promotes oligodendrocyte myelination

Wong

Giuffrida

Wood

et al. 2014

Molecular and Cellular Neuroscience

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“…In this con nection, several laboratories are concerned with the construction of low molecular weight functional BDNF mimetics. Thus, a team of Australian research ers has designed a number of mimetics based on BDNF loops: monomeric monocyclic peptides with the antagonistic activity on the basis of loops 1, 2, and 4 [4,5]; dimeric bicyclic and tricyclic peptides with the agonistic activity based on loop 2 [6]; a cyclopen tapeptide based on the loop 4 tripeptide fragment Lys Lys Arg , which was created as a ligand for the p75 receptor and which enhances the survival of sensory neurons in vitro [7], and its lipophilic derivatives [8].…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of dipeptide mimetics of the brain-derived neurotrophic factor

et al. 2012

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Low-molecular mimetics of brain-derived neurotrophic factor (BDNF) loops 1 and 4 representing to monomeric and dimeric amides of N-acyldipeptides were constructed and synthesized. The sequence of these dipeptides coinside with the central regions of beta-turns of corresponding loops of neurotrophine sequence, and acyl groups are bioisosters of preceding amino acid residues. Hexa- and heptamethylenediamine were used as spacers linking C-terminus ofdipeptides in BDNF dimeric mimetics. These substances were synthesized by classic peptide synthesis methods in solution and got laboratory codes GSB-104 (HO-Suc-Ser-Lys-NH2), GSB-106 ([HO-Suc-Ser-Lys-NH-(CH2)3-]2), GSB-207 (HO-Suc-Met-Ser-NH2) and GSB-214 ([HO-Suc-Met-Ser-NH-(CH2)7/2-]2). By using the culture of immortalized hippocampal cell line HT-22 on the oxidative stress conditions it was shown that dimeric mimetics of both loops demonstrated neuroprotective activity in the concentration rage of 10(-5)-10(-8) M. Monomeric loop 1 mimetic GSB-207 was inactive in the same concentrations and monomeric loop 4 mimetic GSB-104 in a concentration of 10(-7) M decreased survival of neurons. Presence of neuroprotective activity only for dimeric mimetics correlates with the data that BDNF is active only in homodimeric form. As opposed to dimeric mimetic of loop 1 GSB-214, dimeric mimetic of loop 4 GSB-106 demonstrates specific for BDNF antidepressive activity in Porsolt test on rats in doses 0.1 and 1 mg/kg i.p. It is suggested that antidepressive activity of BDNF is associated with its loop 4. We consider that compounds obtained will be useful for investigation of BDNF action mechanism and can lead to creation of a new group of medicinal substances with antidepressive and neuroprotective activities.

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Modified low molecular weight cyclic peptides as mimetics of BDNF with improved potency, proteolytic stability and transmembrane passage in vitro

Cited by 36 publications

References 37 publications

O-Methylated Metabolite of 7,8-Dihydroxyflavone Activates TrkB Receptor and Displays Antidepressant Activity

O-Methylated Metabolite of 7,8-Dihydroxyflavone Activates TrkB Receptor and Displays Antidepressant Activity

TDP6, a brain-derived neurotrophic factor-based trkB peptide mimetic, promotes oligodendrocyte myelination

Design and synthesis of dipeptide mimetics of the brain-derived neurotrophic factor

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