Pharmacokinetic Properties of a Novel d-Peptide Developed to be Therapeutically Active Against Toxic β-Amyloid Oligomers

Leithold, Leonie H. E.; Jiang, Nan; Post, Julia; Ziehm, Tamar; Schartmann, Elena; Kutzsche, Janine; Shah, N. Jon; Breitkreutz, Jörg; Langen, Karl‐Josef; Willuweit, Antje; Willbold, Dieter

doi:10.1007/s11095-015-1791-2

Cited by 39 publications

(41 citation statements)

References 34 publications

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“…protease‐resistant), non‐toxic and can readily penetrate the blood–brain barrier in wildtype mice via different routes of administration (Leithold et al . ; Jiang et al . ).…”

Section: Resultsmentioning

confidence: 99%

Label‐free distribution of anti‐amyloid D‐AIP in Drosophila melanogaster: prevention of Aβ42‐induced toxicity without side effects in transgenic flies

Zhong

Shobo

Hancock

et al. 2019

Journal of Neurochemistry

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Soluble oligomers of the 42‐amino acid amyloid beta (Aβ42) peptide are highly toxic and suspected as the causative agent of synaptic dysfunction and neuronal loss in Alzheimer's disease (AD). Previously, we have shown that a small, D‐amino acid Aβ42‐oligomer interacting peptide (D‐AIP) can neutralize human Aβ42‐mediated toxicity using in vitro and cell‐based assays. In the present longitudinal study using a transgenic Drosophila melanogaster model, advanced live confocal imaging and mass spectrometry imaging (MALDI‐MSI) showed that the eight amino acid D‐AIP can attenuate Aβ42‐induced toxicity in vivo. By separating male and female flies into distinct groups, the resultant distribution of ingested D‐AIP was different between the sexes. The Aβ42‐induced ‘rough eye’ phenotype could be rescued in the female transgenics, likely because of the co‐localization of D‐AIP with human Aβ42 in the female fly heads. Interestingly, the phenotype could not be rescued in the male transgenics, likely because of the co‐localization of D‐AIP with a confounding male‐specific sex peptide (Acp70A candidate in MSI spectra) in the gut of the male flies. As a novel, more cost‐effective strategy to prevent toxic amyloid formation during the early stages of AD (i.e. neutralization of toxic low‐order Aβ42 oligomers without creating larger aggregates in the process), our longitudinal study establishes that D‐AIP is a stable and highly effective neutralizer of toxic Aβ42 peptides in vivo. Cover Image for this issue: doi: .

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“…protease‐resistant), non‐toxic and can readily penetrate the blood–brain barrier in wildtype mice via different routes of administration (Leithold et al . ; Jiang et al . ).…”

Section: Resultsmentioning

confidence: 99%

Label‐free distribution of anti‐amyloid D‐AIP in Drosophila melanogaster: prevention of Aβ42‐induced toxicity without side effects in transgenic flies

Zhong

Shobo

Hancock

et al. 2019

Journal of Neurochemistry

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“…We next sought to investigate whether known inhibitors of human pathological amyloid formation would effectively inhibit CsgA fibrillation on the basis of this proposed structural similarity. We tested a group of synthetic D-enantiomeric peptides (referred to here as D-peptides) designed against Aβ (55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65). Two of the D-peptides tested, ANK6 and DB3DB3 (60), were found to inhibit CsgA fibrillation in dose-dependent manners.…”

Section: Csga Shares Fibrillation Inhibitors With Aβmentioning

confidence: 99%

“…The structural similarity between fibrillar spine segments derived from CsgA and those derived from human pathological amyloids prompted us to investigate whether fibrillation inhibitors designed against human amyloids could also inhibit curli formation. Accordingly, we found that two D-enantiomeric peptides, originally designed to interfere with the formation of oligomers of Alzheimer's disease-associated Aβ (55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65), inhibited the fibrillation of CsgA spines as well as of full-length CsgA and reduced biofilm formation in curli-expressing Salmonella typhimurium in dosedependent manners. These results provide structural insights into a biofilm-related amyloid and pave the way for the rational development of anti-microbial drugs targeting amyloid-structured biofilms.…”

Section: Introductionmentioning

confidence: 99%

Structural Insights into Curli CsgA Cross-β Fibril Architecture Inspired Repurposing of Anti-amyloid Compounds as Anti-biofilm Agents

Perov

Lidor

Salinas

et al. 2018

Preprint

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These authors contributed equally to this work †Correspondence to: mlandau@technion.ac.il Curli amyloid fibrils secreted by Enterobacteriaceae mediate host cell adhesion and contribute to biofilm formation, thereby promoting bacterial resistance to environmental stressors. Here, we present crystal structures of amyloid-forming segments from the major curlin subunit, CsgA, revealing steric zipper fibrils of tightly mated β-sheets, demonstrating a structural link between curli and human pathological amyloids. We propose that these cross-β segments structure the highly robust curli amyloid core. D-enantiomeric peptides, originally developed to interfere with Alzheimer's disease-associated Amyloid-β, inhibited CsgA fibrillation and reduced biofilm formation in Salmonella typhimurium. Moreover, CsgA fibrils cross-seeded fibrillation of Amyloid-β, providing further support for the proposed structural resemblance and potential for cross-species amyloid interactions. In this study, we provide structural insights into curli formation, offer a novel strategy for disrupting amyloid-structured biofilms, and hypothesize on the formation of self-propagating prion-like species originating from a microbial source that could influence neurodegenerative diseases. SignificanceAtomic resolution structural insights into the biofilm-associated curli amyloid fibril secreted by Enterobacteriaceae revealed elements of fibrillar architecture conserved between bacterial and human amyloids. This inspired us to repurpose anti-amyloid drugs designed to target human pathological amyloids as a novel class of anti-biofilm agents. Moreover, the results provide a molecular basis for understanding interspecies cross-seeding of amyloids through the generation of prion-like agents by molecular mimicry. This raises concerns regarding human exposure to exogenous sources of amyloids, such as contaminated food and amyloid-secreting microbes. Overall, we provide a novel framework for investigating interspecies amyloid interactions at the molecular level and offer novel insights into mechanisms which may underlie the evolutionary and etiological relationships between the human and microbial amylomes.

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“…In the past years, we have identified a number of D-enantiomeric peptides as promising drug candidates for direct elimination of A␤ oligo (25)(26)(27)(28)(29)(30). The advantage of D-peptides over L-peptides is their higher protease resistance, resulting in slower degradation and longer half-life (31,32).…”

mentioning

confidence: 99%

“…Treatment with D3 reduces the number of amyloid plaques (26) and improves cognition in transgenic AD mice (28). One derivative of D3 called RD2 shows enhanced binding to A␤ (36, 37), and both RD2 and D3 have demonstrated desirable pharmacokinetic properties (29,38). A further promising derivative is the D-peptide RD2D3, a head-to-tail tandem combination of RD2 and D3 (30,34,39).…”

mentioning

confidence: 99%

A d-enantiomeric peptide interferes with heteroassociation of amyloid-β oligomers and prion protein

Rösener

Gremer

Reinartz

et al. 2018

Journal of Biological Chemistry

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects millions of people worldwide. One AD hallmark is the aggregation of β-amyloid (Aβ) into soluble oligomers and insoluble fibrils. Several studies have reported that oligomers rather than fibrils are the most toxic species in AD progression. Aβ oligomers bind with high affinity to membrane-associated prion protein (PrP), leading to toxic signaling across the cell membrane, which makes the Aβ-PrP interaction an attractive therapeutic target. Here, probing this interaction in more detail, we found that both full-length, soluble human (hu) PrP(23-230) and huPrP(23-144), lacking the globular C-terminal domain, bind to Aβ oligomers to form large complexes above the megadalton size range. Following purification by sucrose density-gradient ultracentrifugation, the Aβ and huPrP contents in these heteroassemblies were quantified by reversed-phase HPLC. The Aβ:PrP molar ratio in these assemblies exhibited some limited variation depending on the molar ratio of the initial mixture. Specifically, a molar ratio of about four Aβ to one huPrP in the presence of an excess of huPrP(23-230) or huPrP(23-144) suggested that four Aβ units are required to form one huPrP-binding site. Of note, an Aβ-binding all-d-enantiomeric peptide, RD2D3, competed with huPrP for Aβ oligomers and interfered with Aβ-PrP heteroassembly in a concentration-dependent manner. Our results highlight the importance of multivalent epitopes on Aβ oligomers for Aβ-PrP interactions and have yielded an all-d-peptide-based, therapeutically promising agent that competes with PrP for these interactions.

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Pharmacokinetic Properties of a Novel d-Peptide Developed to be Therapeutically Active Against Toxic β-Amyloid Oligomers

Abstract: These excellent pharmacokinetic properties confirm that RD2 is a very promising drug candidate for AD.

Cited by 39 publications

References 34 publications

Label‐free distribution of anti‐amyloid D‐AIP in Drosophila melanogaster: prevention of Aβ42‐induced toxicity without side effects in transgenic flies

Label‐free distribution of anti‐amyloid D‐AIP in Drosophila melanogaster: prevention of Aβ42‐induced toxicity without side effects in transgenic flies

Structural Insights into Curli CsgA Cross-β Fibril Architecture Inspired Repurposing of Anti-amyloid Compounds as Anti-biofilm Agents

A d-enantiomeric peptide interferes with heteroassociation of amyloid-β oligomers and prion protein

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