My group pioneered copper-free bioorthogonal “click” reactions on cellular DNA and RNA. In this approach, a bioorthogonal functional group (azide, alkene, or alkyne) is metabolically incorporated into cellular DNA or RNA by endogenous pathways. Subsequent detection is accomplished by adding a fluorescent probe or affinity tag carrying a complementary “click” partner. In cooperation with Sigma Aldrich, we have commercialized compounds from my lab (ex. PNAS 2011, 20404; ChemBioChem 2014, 789) that have been used in over 50 publications by other groups studying regenerative medicine, stem cell biology and precision medicine. My own group discovered that “theranostic” candidates for precision medicine can be generated by introducing a bioorthogonal functional group into the pharmacophore of an FDA-
approved drug such as cytarabine (ara-C) with little or no impact on its potency or mode of action (ex. PNAS 2018, E1366; ACIE 2015, 7911). Using this approach, we discovered that metabolic incorporation of ara-C into DNA was unexpectedly associated with drug resistance rather than drug sensitivity. My group has extensive expertise in the synthesis of chemically-modified oligonucleotides, with ~½ of my research projects over the past 10 years involving the preparation and study fluorescent oligonucleotides (ex. JACS 2010, 18004; NAR 2011, 6825; ACIE 2012, 3466; JACS 2015, 137, 699; ACIE 2018, 15405 etc.). We use a variety of structural biology methods to study covalent and non-covalent binding interactions involving nucleic acids (ex. JACS 2015, 699; ChemComm 2016, 4718; NAR 2018, 6470; Nat. Commun. 2019, 4818).