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

Abstract

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.

In Vitro and In Vivo Efficacies of the Linear and the Cyclic Version of an All-d-Enantiomeric Peptide Developed for the Treatment of Alzheimer’s Disease

“…In order to verify and extend the proteolytic stability/in vitro ADME (absorption, distribution, metabolism and excretion) of RD2D3 and cRD2D3, previously described for tritium labeled d -peptides ( 3 H) [ 15 , 17 ], we performed different tests to investigate the proteolytic stability in different (simulated) body fluids. In both, simulated gastric (SGF) and intestinal fluid (SIF), RD2D3 and cRD2D3 were remarkably stable (RD2D3: SIF 4 h 100%, 8 h 93.5%, SGF 4 h 100%, 8 h 100%, cRD2D3: SIF 4 h 96%, 8 h 87.2%, SGF 4 h 99.5% and 8 h 99.7% Figure 3 a,b).…”

“…administration), high proteolytic stability and therapeutic efficacy by improving the cognitive abilities of transgenic APP Swedish/Dutch/Iowa (Tg-SwDI) AD mice [ 14 , 15 ]. Besides the development of linear tandem- d -peptides, a further approach for a rational drug design was the cyclization of either homo- or tandem- d -peptides [ 16 , 17 ]. For the cyclized tandem- d -peptide cRD2D3, a remarkably enhanced pharmacokinetic profile was found [ 17 ].…”

“…Besides the development of linear tandem- d -peptides, a further approach for a rational drug design was the cyclization of either homo- or tandem- d -peptides [ 16 , 17 ]. For the cyclized tandem- d -peptide cRD2D3, a remarkably enhanced pharmacokinetic profile was found [ 17 ]. Comparing the pharmacokinetic profiles of the linear and cyclic version of the d -peptide RD2D3 (RD2D3 vs. cRD2D3) after intravenous (i.v.).…”

“…administration in C57Bl/6 wild type (WT) mice resulted in a tremendously increased terminal half-life (2.3 vs. 58 h), increased BBB penetration values and brain peptide concentrations of cRD2D3. Furthermore, for cRD2D3 a high oral bioavailability was demonstrated [ 17 ]. Both, a long half-life and high oral bioavailability are extremely advantageous for active ingredients used in the therapy of AD and qualify for daily drug administrations.…”

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

“…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]. With regards to tissue targeting, CARPs and CARP-conjugates generally exhibit preferential distribution in kidney, liver, spleen, lung and to a lesser extent brain [203,204,[210][211][212][213][214][215][216].…”