In this lecture I will describe recent efforts in our laboratory to apply the powerful principles underlying biological evolution to the discovery of bioactive synthetic small molecules.  We developed and applied DNA-templated synthesis to translate libraries of DNA sequences into corresponding synthetic small molecules.  DNA-templated synthesis coupled with in vitro selections resulted in the discovery of new kinase and protease inhibitors with unusual potency and selectivity.  One such macrocycle has revealed new physiological functions and highlighted the therapeutic potential of an important mammalian regulator of glucose homeostasis that has not previously been probed by an inhibitor in vivo.  The insights emerging from the application of this DNA-templated macrocycle have implications for the development of a new class of type-2 diabetes therapeutics.

Integrating chemistry and evolution to illuminate and program biology

247th National Meeting (2014)

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