Structural basis for targeting the human T-cell leukemia virus Tax oncoprotein and syntenin-1 interaction using a small molecule

Abstract

SUMMARYHuman T-cell leukemia virus type-1 (HTLV-1) is the first pathogenic retrovirus discovered in human. Although HTLV-1-induced diseases are well characterized and linked to the encoded Tax-1 protein, there is currently no strategy to target Tax-1 functions with small molecules. Here, we report a comprehensive interaction map between Tax-1 and human PDZ domain-containing proteins (hPDZome), and we show that Tax-1 interacts with one-third of them. This includes proteins involved in cell cycle, cell-cell junction and cytoskeleton organization, as well as in membrane complexes assembly. Using nuclear magnetic resonance (NMR) spectroscopy, we have determined the structural basis of the interaction between the C-terminal PDZ binding motif (PBM) of Tax-1, and the PDZ domains of DLG1 and syntenin-1. Finally, we have used molecular modeling and mammalian cell-based assays to demonstrate that Tax-1/PDZ-domain interactions are amenable to small-molecule inhibition. Thus, our work provides a framework for the design of targeted therapies for HTLV-1-induced diseases.Highlightscomprehensive interactome map of HTLV-1 Tax / human PDZ proteinsbasis of Tax-1 PBM binding to human DLG1 and syntenin-1 PDZ domains”.significance of inhibiting Tax-1 functionsof the Tax-1 / PDZ interfaceGraphical abstract

A systematic approach to identify host targets and rapidly deliver broad-spectrum antivirals

“…This will output a list of high-quality, direct virus-host PPI targets, from which the interacting domains can be predicted in silico using motif-domain and/or domain-domain complementarity approaches, as described in Maseko et al. 20 Indeed, many viral proteins contain short linear motifs (SLiM), which are predicted to bind known complementary host protein domains. Alternatively, structure-based protein-protein docking can be carried out using experimental structures available in the Protein Data Bank or predicted structures in the AlphaFold Protein Structure Database.…”