Discovery of small molecules that modulate transient protein-protein interactions leading to amyloid formation (360G-Wellcome-109154_Z_15_A)
The development of anti-amyloid drugs has been hampered by the mechanistic complexity of amyloid formation pathways. In order to gain a greater understanding of the conformational changes and dynamic motions associated with fibrillogenesis, this project aims to develop and use small molecules to study an archetypical amyloid protein, beta2-microglobulin (beta2m) – specifically, the amyloidogenic truncation variant, DeltaN6. Small molecule fragments which are compatible with site-directed screening methods will be synthesised, so as to allow amyloid-modulating regions of DeltaN6 to be targeted. Hits which are identified in site-directed screens will be optimised as necessary, in order to produce small molecules which are capable of perturbing amyloid formation pathways upon binding. Understanding the link between small molecule-induced changes in DeltaN6 dynamics (to be studied using nuclear magnetic resonance spectroscopy), and changes in the rate and outcome of fibrillogenesis, will provide both beta2m-specific and generic insights into amyloid formation pathways.
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