Project No.2258

Primary Supervisor

Dr Sam Thompson – University of Southampton

Co-Supervisor(s)

Dr Wei-feng Xue – University of Kent

Summary

Despite prolonged and intensive research programmes in academia and industry, the pathogenesis, early diagnosis and treatment of Alzheimer’s, Parkinson’s, type II diabetes, and other amyloidopathies remain unmet impact challenges.

A hallmark of these conditions is the presence of misfolded proteins in which a dysfunctional toxic state is populated. Very limited success has been possible with extant therapeutic approaches that have concentrated on reducing protein production and disrupting amyloid aggregates. In order to tackle these maladies, an improved understanding of the basic science underlying the conditions is required. There are few examples of rationally-designed molecules that target native or prefibrillar protein states, despite increasing evidence to suggest the latter are highly toxic. Moreover, the relationship between protein sequence and the multiple amyloidogenic polymorphs has not been adequately explored. The inability to selectively recognise specific native and non-native proteins and their oligomers also limits the use of imaging agents for early detection and monitoring disease progression. This project will focus on the design, synthesis and testing of synthetic molecules that template or inhibit the formation of specific polymorphs, thus allowing thorough biophysical interrogation, providing atomic- and molecular-level information. We will explore the use of these molecules to modulate protein behaviour by acting as synthetic chaperones, characterising the effect on the kinetics of assembly and their structural organisation. The insights gained may inform molecular strategies to inhibit formation of detrimental amyloid structures. Particular targets will include Ab (Alzheimer’s), a-synuclein (Parkinson’s) and IAPP (type 2 diabetes).