BIOSYNTHESIS AND GENETIC SELECTION OF CYCLIC PEPTIDES WITH POTENTIAL THERAPEUTIC EFFECTS AGAINST ALZHEIMER'S DISEASE: INHIBITORS OF AΒ AGGREGATION

Abstract: 

Alzheimer's disease (AD) is the most common form of dementia, a currently incurable condition which is affecting 28 million people worldwide. AD is thought to be initiated by the misfolding of the amyloid ?² peptide (A?²), which leads to the formation of cytotoxic A?² oligomers and neuron degeneration.

The goal of the present proposal is the discovery of potential therapeutics against AD.

The topic of the proposed research is the directed evolution of short cyclic peptides (molecular weights <650) with the ability to bind to and correct the misfolding of A?², thus inhibiting A?² oligomer formation, neuron degeneration, and the development of AD (CYCLIPAD). The cyclic peptides under investigation will be produced recombinantly in E. coli cells in the form of combinatorial libraries of random sequences. This will allow the facile biosynthesis of a large number of compounds (10^7) exhibiting high levels of chemical and structural diversity. These libraries will then be screened and the rare functional sequences will be identified using a genetic screen comprising bacterial cells expressing A?² fusions with GFP. Due to the misfolding of A?², E. coli-expressed A?²-GFP accumulates into insoluble and non-fluorescent aggregates, and thus cells expressing A?²-GFP lack fluorescence. Bacterial clones expressing peptides that bind to and correct the misfolding of A?², however, will produce soluble A?²-GFP, will acquire a fluorescent phenotype, and will be rapidly isolated using fluorescence-activated cell sorting (FACS). The selected peptides will be synthesized, and their effect on A?² aggregation will be evaluated by biochemical and biophysical analysis. The ability of the identified peptides to inhibit A?² pathology will be examined by evaluating A?²-oligomer-induced toxicity in human neurons and amyloid plaque formation in the brains of transgenic mouse models of AD. Cyclic peptides that correct the misfolding of A?² and inhibit A?² neurotoxicity will become drug candidates against AD.

Project info

Acronym:
CYCLIPAD
Scientific Coordinator:
Gonos Eftstathios
Research Team 2 Leader:
Kolisis Fragiskos
Research Team 3 Leader:
Igglessi-Markopoulou Olga
Research Team 4 Leader:
Efthimiopoulos Spyros

Stats

I.D.:
657
Mis:
380042
Duration (months):
44
Budget:
600 000.00
Diavgeia:
ΑΔΑ: Β4169-ΕΙΧ

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