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Identification of small molecule antivirals against HTLV-1 by targeting the hDLG1-Tax-1 protein-protein interaction
Sibusiso B Maseko1, Yasmine Brammerloo1, Inge Van Molle2
1Laboratory of Viral Interactomes, Unit of Molecular Biology of Diseases, GIGA Institute, University of Liege, Liège, Belgium.
Abstract:
Human 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 oncoprotein, there is currently no strategy to target Tax-1 functions with small molecules. Here, we analyzed the binding of Tax-1 to the human homolog of the drosophila discs large tumor suppressor (hDLG1/SAP97), a multi-domain scaffolding protein involved in Tax-1-transformation ability. We have solved the structures of the PDZ binding motif (PBM) of Tax-1 in complex with the PDZ1 and PDZ2 domains of hDLG1 and assessed the binding of 10 million molecules by virtual screening. Among the 19 experimentally confirmed compounds, one systematically inhibited the Tax-1-hDLG1 interaction in different biophysical and cellular assays, as well as HTLV-1 cell-to-cell transmission in a T-cell model. Thus, our work demonstrates that interactions involving Tax-1 PDZ-domains are amenable to small-molecule inhibition, which provides a framework for the design of targeted therapies for HTLV-1-induced diseases.
Insights
Researchers identified a small molecule that inhibits the interaction between Human T-cell leukemia virus type-1 (HTLV-1) Tax-1 oncoprotein and hDLG1. This discovery offers a new strategy for developing targeted therapies against HTLV-1-induced diseases.
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Human T-cell leukemia virus type-1 (HTLV-1) is the first identified human pathogenic retrovirus.
- HTLV-1-associated diseases are linked to the Tax-1 oncoprotein, but no small-molecule inhibitors targeting Tax-1 functions currently exist.
Purpose of the Study:
- To investigate the interaction between the HTLV-1 Tax-1 oncoprotein and the human homolog of Drosophila discs large tumor suppressor (hDLG1/SAP97).
- To identify small molecules capable of inhibiting the Tax-1-hDLG1 interaction and HTLV-1 transmission.
Main Methods:
- Structural analysis of Tax-1 PDZ-binding motif (PBM) complexed with hDLG1 PDZ1 and PDZ2 domains.
- Virtual screening of 10 million molecules to assess binding affinity.
- Experimental validation of identified compounds using biophysical and cellular assays.
Main Results:
- The structures of Tax-1 PBM in complex with hDLG1 PDZ1 and PDZ2 domains were determined.
- Virtual screening identified potential inhibitors of the Tax-1-hDLG1 interaction.
- One compound demonstrated consistent inhibition of the Tax-1-hDLG1 interaction and HTLV-1 cell-to-cell transmission in cellular models.
Conclusions:
- The interaction between HTLV-1 Tax-1 and hDLG1 PDZ domains is a viable target for small-molecule inhibition.
- This study provides a framework for designing novel targeted therapies for HTLV-1-induced diseases.
