Determining the role of molecular co-chaperones in virus infection: a novel antiviral approach

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Background. Molecular chaperones are essential for protein homeostasis, particularly in cancers. For oncogenic viruses, molecular chaperones function as broad host factors required for viral protein folding and stability, therefore viral proteins are exquisitely sensitive to perturbations in molecular chaperone-related pathways, presenting a novel antiviral target. We have exciting data showing that the molecular co-chaperone, STIP1, is essential for KSHV replication. Objectives. The aim of this project is to determine the role of STIP1 in KSHV biology. We will map the KSHV-STIP1 interactome using affinity-based quantitative proteomics. Moreover, the project will utilize a medicinal chemistry approach to determine if inhibiting molecular co-chaperone function is a potential therapeutic approach for the treatment of this important family of viruses. Here we will identify small molecule inhibitors which prevent STIP1 functioning, using a virtual high-throughput screening campaign. Prioritised compounds will then be screened for KSHV antiviral activity. Therefore this project will determine how virus-mediated manipulation of the host molecular chaperone pathway regulates the viral proteome during virus infection and determine if this is a viable antiviral strategy. Novelty. This project is highly novel. Molecular chaperones are an emerging area of research key to the replication of a wide range of viruses. The project will therefore investigate novel mechanisms utilised by viruses to regulate host cell machinery which can dictate how the virus and host cell proteome is regulated to benefit virus replication.Timeliness. The project is timely as the molecular chaperone machinery is emerging as a key regulator of virus replication, as such it is an attractive antiviral target. Moreover, understanding how viruses manipulate this pathway will provide a better understanding of how alterations in molecular chaperones are associated with human disease.Experimental Approach. The project utilises a multidisiplinary approach and cutting-edge methodology including quantitiative proteomics, bioinformatic analysis, cell biology and medicinal chemistry.