Large-Scale Oral Treatment Study with the Four Most Promising D3-Derivatives for the Treatment of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is associated with the aggregation of the amyloid β protein (Aβ). Aβ oligomers are currently thought to be the major neurotoxic agent responsible for disease development and progression. Thus, their elimination is highly desirable for therapy development. Our therapeutic approach aims at specific and direct elimination of toxic Aβ oligomers by stabilizing Aβ monomers in an aggregation-incompetent conformation. We have proven that our lead compound “D3”, an all d-enantiomeric-peptide, specifically eliminates Aβ oligomers in vitro. In vivo, D3 enhances cognition and reduces plaque load in several transgenic AD mouse models. Here, we performed a large-scale oral proof of concept efficacy study, in which we directly compared four of the most promising D3-derivatives in transgenic mice expressing human amyloid precursor protein with Swedish and London mutations (APPSL), transgenic mice, to identify the most effective compound. RD2 and D3D3, both derived from D3 by rational design, were discovered to be the most effective derivatives in improving cognition in the Morris water maze. The performance of RD2- and D3D3-treated mice within the Morris water maze was significantly better than placebo-treated mice and, importantly, nearly as good as those of non-transgenic littermates, suggesting a complete reversal of the cognitive deficit of APPSL mice.

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

“…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).…”

“…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). RD2D3 binds A␤(1-42) with a K D of 486 Ϯ 69 nM (39).…”

A Novel Anti-inflammatory D-peptide Halts Disease Phenotype Progression in an Als Mouse Model

“…However, RD2RD2 was not signi cantly e cient neither on amyloid load (Fig. 2) nor on cognitive de cits [34]. Instead,we found potent anti-in ammatory effects in the AD mouse model, which was con rmed in the ALS mouse model, although the mechanism of action is not yet clear.…”

“…The compound RD2 binds preferentially amyloid beta (Aβ) monomers with nanomolar a nity and stabilizes Aβ in its native conformation [30], which is a novel strategy to directly disassemble toxic Aβ oligomers into native monomers [31]. RD2 has recently successfully passed a phase I clinical trial in healthy subjects (Single Ascending Doses (SAD) EUDRA-CT: 2017-000396-93 and Multiple Ascending Doses (MAD) EUDRA-CT: 2018-002500-14) [32] after demonstrating its preclinical e cacy in several AD mouse models [33][34][35][36]. The head-to-tail tandem version of RD2, RD2RD2, was designed to obtain a bivalent version of RD2 with potentially higher avidity and a nity for polyvalent Aβ assemblies.…”

A Novel Anti-inflammatory D-peptide Halts Disease Phenotype Progression in an ALS Mouse Model

“…However, RD2RD2 was not signi cantly e cient neither on amyloid load (Fig. 2) nor on cognitive de cits [34].…”