Development of new peptide based NIR probe conjugates for specifically and selectively detecting amyloid early biomarkers

• Applicant: Professor Dr. Norbert Sewald
• Subject Area: Biological and Biomimetic Chemistry
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505429707

FluPepDye aims to provide new selective NIR-fluorescent cyclopeptides for specifically detecting early biomarkers of distinct amyloid pathologies and to translate amyloid-binding fluorophores into useful research or clinical tools for aiding the early and reliable diagnosis of amyloid-related diseases. The project principally focuses on Amyloid β(1-42) peptide (Aβ1-42), involved in Alzheimer’s Disease (AD), and it aims to extend the employed modulable approach to other amyloidogenic proteins such as α-synuclein, tau and hIAPP, involved in other pathologies. While more than 20 amyloid diseases (such as neurodegenerative diseases and type II Diabetes) are known and involve more than 30 amyloid proteins, no early diagnostic tools are currently available for any of these diseases. It is crucial to establish early and precise diagnostics of the type of degeneration before specific symptoms of the disease appear, because when the clinical symptoms are present, the destruction of the target organs and cells (neurons in neurodegenerative diseases and pancreatic β-cells in diabetes) is irreversible. Several efforts have been made in the field of bioimaging using non-invasive NIR probes in the frame of neurodegenerative diseases, particularly for AD diagnosis. Despite their favourable features for their in vivo application, their translation into the clinical practice remains challenging and further optical improvements and technological evolutions are still needed. To our knowledge, none of them has been designed and proven to be specific for only one type of amyloid protein. Furthermore, probes able to detect selectively only soluble oligomers at the pre-clinical stage of neurodegeneration have not been reported to date. This research project will focus on the design, synthesis and evaluation of new peptide based NIR probe conjugates. These new fluorescent molecules are conceived to have suitable emission wavelengths with turn-on optical properties, selectivity for one specific amyloid protein and its soluble early aggregate species, high stability in biological environments, and good permeability across membranes. The new peptide-based probe conjugates will be composed by three elements: a cyclopeptide as recognition element that will drive the selectivity for a specific amyloid protein and for oligomer species, a tryptophan as anchor element for conjugation by palladium catalysed cross-coupling reactions and a fluorescent probe as tracer element providing tailored NIR fluorescence. These probes will be evaluated in biophysical assays to get information on their fluorescent properties, their affinity of binding, their selectivity, their metabolic stability, and their membrane permeability.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Professor Dr. Nicolo Tonali