Preclinical Pharmacokinetic Studies of the Tritium Labelled D-Enantiomeric Peptide D3 Developed for the Treatment of Alzheimer´s Disease

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

doi:10.1371/journal.pone.0128553

Cited by 34 publications

(42 citation statements)

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“…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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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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“…Previously, we have developed the all-D-enantiomeric peptide D3, which specifically eliminates neurotoxic Aβ oligomers in vitro (Brener et al, 2015;Funke and Willbold, 2012), has a high oral bioavailability (Jiang et al, 2015) and is therapeutically active in vivo (van Groen et al, 2012;van Groen et al, 2013;van Groen et al, 2008) even after oral administration (Funke et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Hence, monitoring the degradation for 24 h was more than sufficient to get an impression of D3's stability in the gastrointestinal tract. The terminal half-life of orally administered D3 in plasma has been shown to be >24 h in a pharmacokinetic study (Jiang et al, 2015). We incubated D3 in plasma even for 20 days.…”

Section: Discussionmentioning

confidence: 99%

“…In studies with AD transgenic mice, D3 reduced the Aβ plaque load as well as cerebral inflammation and showed an improvement in cognition (van Groen et al, 2012;van Groen et al, 2013;van Groen et al, 2008) even after oral administration (Funke et al, 2010). A pharmacokinetic study with the tritiated peptide revealed that D3 is characterized by high oral bioavailability, long blood circulation (Jiang et al, 2015) and efficient blood brain barrier permeability (Liu et al, 2010). The high oral bioavailability is based on an efficient intestinal absorption and probably also on a high resistance against metabolization during the gastrointestinal passage.…”

Section: Introductionmentioning

confidence: 99%

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Surprisingly high stability of the Aβ oligomer eliminating all-d-enantiomeric peptide D3 in media simulating the route of orally administered drugs

Elfgen

Santiago‐Schübel

Gremer

et al. 2017

European Journal of Pharmaceutical Sciences

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The aggregation of the amyloid β protein (Aβ) plays an important role in the pathology of Alzheimer's disease. Previously, we have developed the all-d-enantiomeric peptide D3, which is able to eliminate neurotoxic Aβ oligomers in vitro and improve cognition in a transgenic Alzheimer's disease mouse model in vivo even after oral administration. d-Peptides are expected to be more resistant against enzymatic proteolysis compared to their l-enantiomeric equivalents, and indeed, a pharmacokinetic study with tritiated D3 revealed the oral bioavailability to be about 58%. To further investigate the underlying properties, we examined the stability of D3 in comparison to its corresponding all-l-enantiomeric mirror image l-D3 in media simulating the gastrointestinal tract, blood and liver. Potential metabolization was followed by reversed-phase high-performance liquid chromatography. In simulated gastric fluid, D3 remained almost completely stable (89%) within 24h, while 70% of l-D3 was degraded within the same time period. Notably, in simulated intestinal fluid, D3 also remained stable (96%) for 24h, whereas l-D3 was completely metabolized within seconds. In human plasma and human liver microsomes, l-D3 was metabolized several hundred times faster than D3. The remarkably high stability may explain the high oral bioavailability seen in previous studies allowing oral administration of the drug candidate. Thus, all-d-enantiomeric peptides may represent a promising new compound class for drug development.

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“…Most studied amyloid beta (Aβ) peptides includes Aβ (1-16), Aβ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), Aβ (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), Aβ (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33), Aβ , Aβ (23-34), Aβ (34)(35)(36)(37)…”

Section: Racemization Of the Aβmentioning

confidence: 99%

Chiral Interface of Amyloid Beta (Aβ): Relevance to Protein Aging, Aggregation and Neurodegeneration

2020

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Biochirality is the subject of distinct branches of science, including biophysics, biochemistry, the stereochemistry of protein folding, neuroscience, brain functional laterality and bioinformatics. At the protein level, biochirality is closely associated with various post-translational modifications (PTMs) accompanied by the non-equilibrium phase transitions (PhTs NE ). PTMs NE support the dynamic balance of the prevalent chirality of enzymes and their substrates. The stereoselective nature of most biochemical reactions is evident in the enzymatic (Enz) and spontaneous (Sp) PTMs (PTMs Enz and PTMs Sp ) of proteins. Protein chirality, which embraces biophysics and biochemistry, is a subject of this review. In this broad field, we focus attention to the amyloid-beta (Aβ) peptide, known for its essential cellular functions and associations with neuropathology. The widely discussed amyloid cascade hypothesis (ACH) of Alzheimer's disease (AD) states that disease pathogenesis is initiated by the oligomerization and subsequent aggregation of the Aβ peptide into plaques. The racemization-induced aggregation of protein and RNA have been extensively studied in the search for the contribution of spontaneous stochastic stereo-specific mechanisms that are common for both kinds of biomolecules. The failure of numerous Aβ drug-targeting therapies requires the reconsolidation of the ACH with the concept of PTMs Sp . The progress in methods of chiral discrimination can help overcome previous limitations in the understanding of AD pathogenesis. The primary target of attention becomes the network of stereospecific PTMs that affect the aggregation of many pathogenic agents, including Aβ. Extensive recent experimental results describe the truncated, isomerized and racemized forms of Aβ and the interplay between enzymatic and PTMs Sp . Currently, accumulated data suggest that non-enzymatic PTMs Sp occur in parallel to an existing metabolic network of enzymatic pathways, meaning that the presence and activity of enzymes does not prevent non-enzymatic reactions from occurring. PTMs Sp impact the functions of many proteins and peptides, including Aβ. This is in logical agreement with the silently accepted racemization hypothesis of protein aggregation (RHPA). Therefore, the ACH of AD should be complemented by the concept of PTMs Sp and RHPA.

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Preclinical Pharmacokinetic Studies of the Tritium Labelled D-Enantiomeric Peptide D3 Developed for the Treatment of Alzheimer´s Disease

Cited by 34 publications

References 31 publications

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

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

Surprisingly high stability of the Aβ oligomer eliminating all-d-enantiomeric peptide D3 in media simulating the route of orally administered drugs

Chiral Interface of Amyloid Beta (Aβ): Relevance to Protein Aging, Aggregation and Neurodegeneration

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