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Macrocyclic Inhibitory Peptide with Potent Anti-amyloid Effect in Alzheimer’s Animal Model

Ref-Nr: TA-B78094


Kurzfassung

  • Macrocyclic peptides with drug-like properties
  • Highly potent inhibitors of Aβ amyloid self-assembly
  • Promising in vivo data from Alzheimer’s mouse model

Hintergrund

Despite the established association between the pathogenesis of Alzheimer’s disease (AD) and the presence of amyloid plaques of β‐amyloid peptide (Aβ) in the brain, all anti‐Aβ therapeutic strategies, mostly representing antibody-based approaches aiming at blocking amyloid self-assembly have so far failed. However, the development of anti-amyloid compounds is an important target of AD-related research. For this reason, there is an urgent need to develop novel classes of amyloid inhibitors.

 


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Lösung

Here, we present synthetic medium sized macrocyclic peptides, termed macrocyclic inhibitory peptides (MCIPs), as a new class of highly potent inhibitors of amyloid self-assembly and related cytotoxic effects¹.The drug-like properties of our lead MCIP 2E include their small size (<20 amino acids), high solubility, potent amyloid inhibitor function (nanomolar IC50) and Aβ40(42) binding affinity, target selectivity, good proteolytic stability in human plasma (in vitro) und BBB permeability (determined using in vitro models), and make them suitable drug candidates. For instance, one of the weak points of the antibodies is their extremely low BBB permeability.


Vorteile

 

 


Anwendungsbereiche

Our lead macrocyclic peptide 2E was confirmed as a potent inhibitor of amyloidogenesis in several in vitro assays1 and a mouse model of Alzheimer’s disease (unpublished data):

 

  • MW < 2000 Da
  • Cost-effective production by routine solid phase peptide synthesis
  • High solubility
  • High Aβ40(42) binding affinity and amyloid inhibitor potency (nanomolar IC50)
  • Good proteolytic stability in human plasma (in vitro)
  • Effective crossing of human blood brain barrier (BBB) (in cell model)
  • Promising data from behavioral tests with no observed in vivo toxicity in mouse model

 


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