IDENTIFICATION AND DEVELOPMENT OF COMPOUNDS THAT ANTAGONIZE JCV HOST CELL RECOGNI

Brown University, Providence RI

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Abstract

JC virus (JCV] is a common human polyomavirus that infects over 70% of the population worldwide. JCV has a restricted cell tropism that is partly due to the initial interaction between the virus and sialic acid containing host cell receptors. We have identified the molecular determinants for interaction between the virus and its cellular receptor, using a combined approach of site-directed mutagenesis and homology-based molecular modeling. Here, we propose incorporating the JCV sialic acid binding domain onto 4-helix bundle proteins, providing a soluble platform for in-depth biophysical characterization of the virus/sialic acid association as well as screening of compounds for potent inhibitors. Preliminary results indicate that the protein platform is a potent inhibitor of JC viral infection and competes with the virus for cell surface receptors. We propose to further characterize the protein template, including comparing the results from mutagenesis studies to those previously carried out for the intact virus. Initial structural studies, employing circular dichroism and highresolution NMR of 15N and 13C enriched samples, display a stable, folded protein and the expected sialic acid binding profile. The structure of the protein template while associated with sialic acid will be determined by NMR, providing the insight for rational design of inhibitors for the association of JCV with its host cell. The JCV templates will also be developed for screening of small compound libraries. Molecules produced from these efforts will allow us to further probe the pathogenesis of JCV induced disease and may lead to novel therapies