Abstract
Multiple sources of evidence suggest that soluble amyloid β (Aβ)-oligomers are responsible for the development and progression of Alzheimer’s disease (AD). In order to specifically eliminate these toxic Aβ-oligomers, our group has developed a variety of all-d-peptides over the past years. One of them, RD2, has been intensively studied and showed such convincing in vitro and in vivo properties that it is currently in clinical trials. In order to further optimize the compounds and to elucidate the characteristics of therapeutic d-peptides, several rational drug design approaches have been performed. Two of these d-peptides are the linear tandem (head-to-tail) d-peptide RD2D3 and its cyclized form cRD2D3. Tandemization and cyclization should result in an increased in vitro potency and increase pharmacokinetic properties, especially crossing the blood–brain-barrier. In comparison, cRD2D3 showed a superior pharmacokinetic profile to RD2D3. This fact suggests that higher efficacy can be achieved in vivo at equally administered concentrations. To prove this hypothesis, we first established the in vitro profile of both d-peptides here. Subsequently, we performed an intraperitoneal treatment study. This study failed to provide evidence that cRD2D3 is superior to RD2D3 in vivo as in some tests cRD2D3 failed to show equal or higher efficacy.
Highlights
Our society is aging and, with it, the number of diseases of old age, especially dementias, are increasing [1]
Aβ is the product of the proteolytic processing of the amyloid precursor protein (APP), which is cleaved by β- and γ-secretases, resulting in Aβ-monomers
The Cyclic D-Peptide cRD2D3 Revealed Increased In Vitro Potency Compared to the Linear
Summary
Our society is aging and, with it, the number of diseases of old age, especially dementias, are increasing [1]. Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and the most common form of dementia worldwide. Its clinical symptoms are considered to be disturbances of memory, language, spatial and temporal orientation and cognitive decline. Aβ is the product of the proteolytic processing of the amyloid precursor protein (APP), which is cleaved by β- and γ-secretases, resulting in Aβ-monomers. These monomers aggregate into Aβ-oligomers and insoluble Aβ-fibrils, which compact further into senile Aβ-plaques [2,3]. It was assumed that Aβ-plaques were responsible for the disease and the cognitive decline of affected patients. The aforementioned soluble Aβ-oligomers are regarded as more than merely an intermediate on their way from monomers to plaques
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