Notch signaling plays important roles in throughout development; from effects on growth, survival, differentiation, to proliferation. The strength of the Notch signal is highly context dependant, and abnormal Notch signaling has been implicated in many diseases, specifically, cancers. For example, a large part of all T-cell acute lymphoblastic leukemias have mutations that activate the Notch 1 receptor.<br/>Previously, studying the Notch receptor, and its inhibition, has mainly focused on canonical ligands that recognize the receptor and blocking signaling with small molecules, peptides, or antibodies. These have achieved global inhibition of Notch signaling, which led to off-target toxicities. To find an antagonist to Notch signaling we screened a phage library and identified several peptide sequences that recognize Notch1. Our preliminary data demonstrated Notch1 staining overlaps with bacteriophage staining on Notch1 upregulated cells. Also, we are able to conjugate dyes directly to the phage, and the phage that displays one of the hit sequences directly binds to cells that overexpress Notch1 and not Notch2 or Notch3. Furthermore, we have shown, through immunoprecipitation, that when we pull down the bacteriophage we are able to find Notch1. Lastly, we show that the peptide is a partial inhibitor of Notch1 signaling. Our next step will be to synthesize a dendritic core molecule that will be able to display the peptide sequence in a similar fashion as on the surface of the bacteriophage. This will help us understand the mechanism of binding and inhibition of the bacteriophage on Notch1.

Discovery and characterization of notch1 modulating peptides

254th National Meeting (2017)

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