Directed Evolution of a Beta-Sheet Scaffold for Targeting Proteins Involved in Human Disease - Thrombin and the Vascular Endothelial Growth Factor (VEGF)
Committee ChairGhosh, Indraneel
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PublisherThe University of Arizona.
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AbstractAberrant protein-protein interactions have been implicated in numerous human diseases. Hence it becomes important to understand the physicochemical basis of these interactions as well as to develop methods to selectively target these protein surfaces. However, it is difficult to target such protein surfaces by small molecules as these surfaces (≥ 600 Å²) are large and flat. We demonstrate the feasibility of utilizing a small beta-sheet scaffold for targeting thrombin as proof of principle. Thrombin is a trypsinlike serine protease generated in the penultimate step of the blood coagulation cascade. Thrombin has numerous potential interaction sites to test our methodology. This strategy was further extended to target the Vascular Endothelial Growth Factor (VEGF). VEGF is a disulfide-linked cytokine that exerts its activity by binding to two high affinity receptors. VEGF has been implicated in angiogenesis where the growth of new blood capillaries provides nourishment to tumor cells and damage delicate retinal tissues. This will help us to develop a new scaffold and provide essential chemical and structural information necessary for binding these discrete protein surfaces. Furthermore, this facilitates the subsequent transfer of minimal epitope information to a small molecule.