Comparison of blood-brain barrier penetration efficiencies between linear and cyclic all-d-enantiomeric peptides developed for the treatment of Alzheimer's disease

Schartmann, Elena; Schemmert, Sarah; Ziehm, Tamar; Leithold, Leonie H. E.; Jiang, Nan; Tusche, Markus; Shah, N. Jon; Langen, Karl‐Josef; Kutzsche, Janine; Willbold, Dieter; Willuweit, Antje

doi:10.1016/j.ejps.2017.12.005

Cited by 11 publications

(18 citation statements)

References 40 publications

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“…In this context, the cyclic peptide (cANK6r) revealed higher brain levels than its linear equivalent (ANK6) or the tandem -peptide (tANK6) after i.v. administration, again substantiating the previously set up hypothesis that cyclization results in more efficient BBB permeation [ 25 ]. Finally, regarding the C max values in plasma as well as in brain for both administration routes, cANK6r always revealed the highest values suggesting and confirming high stability and enhanced abilities to cross membranes.…”

Section: Discussionsupporting

confidence: 86%

“…Another optimization approach, which aimed to increase blood-brain barrier permeation, revealed the 13-mer cANK6r. Previously, it had been shown that cyclic isoforms of several D3-derivatives reached remarkably higher brain levels after administration to wild type mice as compared to the corresponding linear peptides [ 25 ]. Consequently, we included cANK6r in this study to find out whether cyclization had an impact on ANK6’s in vitro potency and whether cyclization, here, also led to higher brain levels in comparison to the originally selected linear peptide although it contains six amino acid residue substitutions as compared to D3.…”

Section: Discussionmentioning

confidence: 99%

“…This has been described and evaluated several times before [ 20, 25, 26, 29 ]. As each -peptide’s 3 H-label was located in a leucine alkyl group (4,5- 3 H- -Leu), the labels were also considered to be biologically stable [ 25 ]. Further underlining the -peptides’ stabilities, Elfgen et al confirmed this by incubation in several media simulating the oral administration route with HPLC analyses [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

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In Vitro Potency and Preclinical Pharmacokinetic Comparison of All-D-Enantiomeric Peptides Developed for the Treatment of Alzheimer’s Disease

Schartmann

Schemmert

Niemietz

et al. 2018

JAD

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Diffusible amyloid-β (Aβ) oligomers are currently presumed to be the most cytotoxic Aβ assembly and held responsible to trigger the pathogenesis of Alzheimer’s disease (AD). Thus, Aβ oligomers are a prominent target in AD drug development. Previously, we reported on our solely -enantiomeric peptide D3 and its derivatives as AD drug candidates. Here, we compare one of the most promising D3 derivatives, ANK6, with its tandem version (tANK6), and its head-to-tail cyclized isoform (cANK6r). In vitro tests investigating the -peptides’ potencies to inhibit Aβ aggregation, eliminate Aβ oligomers, and reduce Aβ-induced cytotoxicity revealed that all three -peptides efficiently target Aβ. Subsequent preclinical pharmacokinetic studies of the three all--peptides in wildtype mice showed promising blood-brain barrier permeability with cANK6r yielding the highest levels in brain. The peptides’ potencies to lower Aβ toxicity and their remarkable brain/plasma ratios make them promising AD drug candidates.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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In Vitro Potency and Preclinical Pharmacokinetic Comparison of All-D-Enantiomeric Peptides Developed for the Treatment of Alzheimer’s Disease

Schartmann

Schemmert

Niemietz

et al. 2018

JAD

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“…The pharmacokinetic characteristics including blood-brain barrier (BBB) penetration ability for RD2RD2 have not been determined, yet. However, for closely related compounds (RD2 and other derivatives), the pharmacokinetic profile and sufficient uptake into the brain have already been demonstrated [37,[50][51][52]. Additionally, the BBB is known to be compromised in SOD1*G93A mice [53,54] allowing higher brain penetration as compared to wildtype mice.…”

Section: Discussionmentioning

confidence: 99%

A Novel Anti-Inflammatory d-Peptide Inhibits Disease Phenotype Progression in an ALS Mouse Model

et al. 2021

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by selective neuronal death in the brain stem and spinal cord. The cause is unknown, but an increasing amount of evidence has firmly certified that neuroinflammation plays a key role in ALS pathogenesis. Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and has been implicated as driver of disease progression. Here, we describe a treatment study demonstrating the therapeutic potential of a tandem version of the well-known all-d-peptide RD2 (RD2RD2) in a transgenic mouse model of ALS (SOD1*G93A). Mice were treated intraperitoneally for four weeks with RD2RD2 vs. placebo. SOD1*G93A mice were tested longitudinally during treatment in various behavioural and motor coordination tests. Brain and spinal cord samples were investigated immunohistochemically for gliosis and neurodegeneration. RD2RD2 treatment in SOD1*G93A mice resulted not only in a reduction of activated astrocytes and microglia in both the brain stem and lumbar spinal cord, but also in a rescue of neurons in the motor cortex. RD2RD2 treatment was able to slow progression of the disease phenotype, especially the motor deficits, to an extent that during the four weeks treatment duration, no significant progression was observed in any of the motor experiments. Based on the presented results, we conclude that RD2RD2 is a potential therapeutic candidate against ALS.

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“…While free CARPs are likely to have a serum half-life of several minutes, CARPs bound to serum proteins are likely to have a serum half-life of several hours [202][203][204][205]. For example, serum proteins such as albumin and α1-acid glycoprotein bind CARPs, providing a reservoir of the peptide that prolongs serum half-life and potentially extending peptide therapeutic duration [203,206,207]. Furthermore, various peptide structural modifications such as cyclization and use of D-enantiomer amino acids can enhance resistance to serum proteases, and thus improve serum stability [206,208,209].…”

Section: Pharmacokinetics Of Carpsmentioning

confidence: 99%

Mitochondria and neuroprotection in stroke: Cationic arginine-rich peptides (CARPs) as a novel class of mitochondria-targeted neuroprotective therapeutics

MacDougall

Anderton

Mastaglia

et al. 2019

Neurobiology of Disease

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Stroke is the second leading cause of death globally and represents a major cause of devastating long-term disability. Despite sustained efforts to develop clinically effective neuroprotective therapies, presently there is no clinically available neuroprotective agent for stroke. As a central mediator of neurodamaging events in stroke, mitochondria are recognised as a critical neuroprotective target, and as such, provide a focus for developing mitochondrial-targeted therapeutics. In recent years, cationic arginine-rich peptides (CARPs) have been identified as a novel class of neuroprotective agent with several demonstrated mechanisms of action, including their ability to target mitochondria and exert positive effects on the organelle. This review provides an overview on neuronal mitochondrial dysfunction in ischaemic stroke pathophysiology and highlights the potential beneficial effects of CARPs on mitochondria in the ischaemic brain following stroke.

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Comparison of blood-brain barrier penetration efficiencies between linear and cyclic all-d-enantiomeric peptides developed for the treatment of Alzheimer's disease

Cited by 11 publications

References 40 publications

In Vitro Potency and Preclinical Pharmacokinetic Comparison of All-D-Enantiomeric Peptides Developed for the Treatment of Alzheimer’s Disease

In Vitro Potency and Preclinical Pharmacokinetic Comparison of All-D-Enantiomeric Peptides Developed for the Treatment of Alzheimer’s Disease

A Novel Anti-Inflammatory d-Peptide Inhibits Disease Phenotype Progression in an ALS Mouse Model

Mitochondria and neuroprotection in stroke: Cationic arginine-rich peptides (CARPs) as a novel class of mitochondria-targeted neuroprotective therapeutics

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