Funds are requested to purchase a Biacore T200 benchtop Surface Plasmon Resonance (SPR) label-free detection system. Wistar investigators have identified an urgent need for this technology in order to support NIH funded research to study structure function relationships between protein: protein, protein: nucleic acid, and small molecule ligand: protein interactions with critical implications to our fundamental understanding of tumor cell biology, treatment, drug resistance, tumor recurrence, and metastasis. The Wistar Institute does not have an instrument with the capabilities of the Biacore T200 and direct access to this technology within our research community is limited as a shared resource. The Wistar Molecular Screening Laboratory was established to enable its scientists to screen small molecule chemical libraries in high-density microtiter plates enhance chemical biology and translation medicine in our research programs and foster new collaborative research and academic-commercial partnerships. The current laboratory infrastructure enables investigators to identify molecules that affect the activity of a target via a labeled (i.e. radioactive, fluoresent, chemiluminescent) tracer/substrate. Although readouts from labeled substrates are very sensitive and amenable to high-throughput, they are also prone to interference, leading to increased false-positive and - negative discovery rates, and provide no evidence that modulators directly bind to the target of interest. Since its inception, the laboratory has facilitted the assay development and execution of small molecule screens against 10 different targets, including gamma Herpes Virus latency, Human Papillomavirus oncoproteins, p53, and human telomerase. The results from these screens have led to the identification of 2-3 series of confirmed """"""""hits"""""""" for each project that are ready for optimization through medicinal chemistry. However, existing technology (i.e. ITC, sedimentation equilibrium by analytical ultracentrifugation) are lower throughput and require large amounts of rare or sensitive materials to assess interactions between the small molecule and target. As such, the requested Biacore T200 will be located and maintained in the Wistar Institute Molecular Screening Facility. The sensitivity, versatility, and throughput of the Biacore T200 will immediately impact the ability of6 Major NIH-funded users and a group of Minor users to quantitatively evaluate a broad spectrum of biomolecular interactions and develop Fragment Based Screening, as an alternative to small molecule inhibitors of protein function. An internal advisory committee comprised of users and senior staff from the Wistar Institute will oversee the operation, maintenance, and equitable access to this instrument. In this application, we present projects and preliminary data from studies that require access to sensitivity of Surface Plasmon Resonance label-free detection. The purchase of the Biacore T200 will greatly enhance the ability of investigators to characterize biomolecular interactions and expand the capabilities and versatility of the Wistar Molecular Screening Facility to support transformative research aimed to reduce the burden of human disease.
