Synthesis and evaluation of new scaffolds to control protein-protein and protein-dna interactions

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The principal focus for my research group is the synthesis and biological evaluation of scaffolds for the modulation of protein-protein or protein-DNA interactions. All of our projects have defined biological goals, but it is the underlying chemical synthesis that most interests us. In an effort to maximize student training, we intentionally choose difficult synthetic targets (whether natural products or designed molecules) that force us to invent new synthetic methodology. Through the process of answering these arduous synthetic challenges, my students become experts in synthetic organic chemistry, leaving them well-prepared for careers in both industry (particularly the pharmaceutical and biotechnology sectors) and academia. In one suite of projects, we are developing an interative synthesis of a new class of non-peptidic molecules that will mimic the surface of an antiparallel ß-sheet, thus facilitating the disruption of "face-on" ß-sheet / ß-sheet interactions. Our end-goal in the most central of these projects involves the disruption of the PD1-PDL1 interaction as a means to treat pancreatic cancer - a disease with a particularly low 5-year survival rate (6% in Canada). Continuing with the iterative synthesis theme, we have also developed a new route to a class of previously un-synthesized natural products from hop plants that are activators of PPAR transcription factors, and have a range of interesting biological properties. In a second suite of projects, we have taken inspiration from a natural product HIV protease inhibitor called didemnaketal A, which is believed to function by disrupting the protease homo-dimer's intercalative ß-sheet. Efficient disruption of intercalative ß-sheets represents a fantastic challenge, and a drug molecule that functions in this way would be a useful add-on to existing HIV drug cocktails. Indeed, the co-administration of a dissociative inhibitor along with a traditional enzyme active-site inhibitor would be an effective means to curtail evolved drug-resistance. Because we don't yet know precisely how didemnaketal binds to HIV protease, we've chosen to first approach this problem as a total synthesis.