DELUGE BIOTECHNOLOGIES INC — Department of Health and Human Services SBIR Phase I: 400

Description

Project Summary Fragment based drug discovery programs begin with the identification of low molecular compounds that bind weakly to the protein of interest (POI). POI-binding fragments are then elaborated and/or linked together to provide lead compounds. Current methods for screening fragment libraries have low throughput and many require large amounts of the POI, often in isotopically labeled form. This proposal will establish a novel screening platform capable of analyzing hundreds of potential fragment-protein interactions in a single tube. We will create dozens of fluorescently encoded one bead one compound (OBOC) libraries comprised of hundreds of low molecular weight compounds. They will be screened against a fluorescently labeled, tetrameric form of the POI. Avidity effects will stabilize the weak interactions sufficiently to allow the beads to be analyzed by flow cytometry, identifying those capable of retaining the POI. If necessary, proximity labeling will be explored to increase the sensitivity of the system. This technology will be employed to discover novel fragments that engage the VHL E3 Ubiquitin ligase.