Development of LA1011 for high affinity binding to Hsp90 for use towards healthy ageing in patients showing Alzheimer's symptoms

With 50 million global cases of Alzheimer's disease (AD) and care costs of 1 trillion UK pounds (expected to triple by 2050), there is a pressing need to slow disease progression, sustain productive lives and reduce costs. We have shown that LA1011 eliminates neurodegeneration in an AD mouse model and identified the Hsp90-FKBP51 complex as the molecular target.

There are three project aims: A). A structure-based design of LA1011 to improve Hsp90 binding. B).

Using biochemical, biophysical and cellular approaches, we will evaluate the importance of FKBP51 and other cochaperones (Aha1, FKBP52 etc) involved in the phosphorylation of Tau, which also compete with LA1011 for Hsp90 binding. C). LipidArt (our industrial partner) are uniquely placed to investigate whether LA1011 alters the membrane physical state, organization and effects on the lipidom and cause the co-induction effect of LA1011. This is a very relevant question since FKBP51 is involved in adipogenesis and lipid metabolism.

There is potential that full AD onset could be prevented by developing LA1011. LA1011 may be applicable to other chaperone dependant neurodegenerative diseases. LA1011 is a useful reagent for use to better understand the complex nature of the Hsp90 mechanism per se, but also in the context of a variety of other diseases (from inflammation to cancer). The project offers an excellent multidisciplinary training opportunity