Chemical Tools to Interrogate Protein-Misfolding Diseases

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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 challenges. A hallmark of these conditions is the presence of misfolded proteins in which dysfunctional toxic states are 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. The relationship between protein sequence, conformational dynamics and their multiple amyloidogenic polymorphs has not been adequately explored. We have demonstrated selective recognition of specific conformational states of prefibrillar amyloigogenic proteins using structure guided rationally designed chemical tools, see for example Chem Commun (2022) 58, 5132. Leveraging the recent explosion in atomic level structural information of amyloid polymorphs, see for example JMB (2021) 433, 167,124, 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 using ThT, CD and AFM. 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. Such transformative technologies will inform molecular strategies to inhibit formation of detrimental amyloid structures and thus push the boundaries of bioscience discovery. Specific targets will include Abeta (Alzheimer's), alpha-synuclein (Parkinson's) and IAPP (type 2 diabetes).