Targeting type-1 diabetes with novel small molecules

We have recently discovered (unpublished) that deletion of a gene encoding a member of the TRP channel family protects mice from streptozotocin-induced diabetes by preventing destruction of insulin secreting β-cells. The mice are otherwise normal indicating that inhibitors of the channel could serve as potential therapeutics for type-1 diabetes. Unpublished in vitro studies, indeed, demonstrated that inhibition of the TRP channel reduces β-cell apoptosis. However, there are no specific channel blockers for this TRP channel. With the aid of the Medicinal Chemistry and Chemical Biology Technology Group and the BHRC, we have screened an in-house chemical library and identified several new structurally diverse compounds that inhibit the TRP channel with IC50s in the sub-micromolar range.

The aim of the study is to test the therapeutic potential of these compounds in preventing β-cell death using in vivo mouse models and in vitro cell- and tissue-based assays. If compounds prove to be toxic, attempts will be made to reduce the toxicity while maintaining or increasing the potency. The potency of the channel blockers will be examined by electrophysiology and calcium imaging. Specificity of promising compounds will be examined on structurally related and human ERG channels expressed in HEK293 cells. The mechanism of their action will be examined by cell biological and biochemical approaches.

These aims will be achieved using an integrated interdisciplinary approach involving techniques in molecular cell biology, biochemistry, electrophysiology, chemistry and in vivo biology.