[en] 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.
Van Molle, Inge ; VIB-VUB Center for Structural Biology, Flemish Institute of Biotechnology (VIB), Brussels, Belgium
Sogues, Adrià ; VIB-VUB Center for Structural Biology, Flemish Institute of Biotechnology (VIB), Brussels, Belgium
Martin, Charlotte; Research Group of Organic Chemistry, Vrije Universiteit Brussel (VUB), Brussels, Belgium
Gorgulla, Christoph ; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA, Department of Physics, Faculty of Arts and Sciences, Harvard University, Cambridge, MA, USA, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
Plant, Estelle ; Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), Gosselies 6041, Belgium
Olivet, Julien ; Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Viral Interactomes Network
Blavier, Jeremy ; Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Viral Interactomes Network
Ntombela, Thandokuhle ; School of Chemistry, University of Witwatersrand, South Africa
Delvigne, Frank ; Université de Liège - ULiège > TERRA Research Centre > Microbial technologies
Arthanari, Haribabu; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA, Department of Physics, Faculty of Arts and Sciences, Harvard University, Cambridge, MA, USA, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
El Hajj, Hiba; Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
Bazarbachi, Ali; Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
Van Lint, Carine; Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), Gosselies 6041, Belgium
Salehi-Ashtiani, Kourosh ; Laboratory of Algal Synthetic and Systems Biology, Division of Science and Math, New York University of Abu Dhabi, Abu Dhabi United Arab Emirates
Remaut, Han ; VIB-VUB Center for Structural Biology, Flemish Institute of Biotechnology (VIB), Brussels, Belgium
Ballet, Steven ; Research Group of Organic Chemistry, Vrije Universiteit Brussel (VUB), Brussels, Belgium
Volkov, Alexander N ; VIB-VUB Center for Structural Biology, Flemish Institute of Biotechnology (VIB), Brussels, Belgium, Jean Jeener NMR Centre, Vrije Universiteit Brussel (VUB), Brussels Belgium. Electronic address: ovolkov@vub.be
Twizere, Jean-Claude ; Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Viral Interactomes Network
This work was primarily supported by the FRS-FNRS Televie grants 30823819 to J-C.T. C.VL., J-C.T. and S.M. are respectively, “Directrice de Recherche”, “Maitre de Recherche” and “Charge de Recherche” of the F.R.S.-FNRS. J-C.T is a visiting research professor at NYUAD. E.P. was a doctoral fellow from the « Télévie » program of the F.R.S.-FNRS and the “Fondation Rose et Jean Hoguet” and next a postdoctoral fellow of Apex Biosolutions (France). S M is further supported by the Funds Suzanne Dechesne, Serge Rousseau and Docteur Jean Gerald, Managed by King Boudouin Foundation. C.M. and S.B. are supported through the Strategic Research Programme (SRP50) of the Vrije Universiteit Brussel. A.S. is supported by a post-doctoral fellowship from the EMBO (ALTF- 709–2021). C.VL. acknowledges funding from the Belgian National Fund for Scientific Research (F.R.S-FNRS, Belgium; grant J.0021.17); the “Télévie” program of the F.R.S.-FNRS; the “Fondation Roi Baudouin”; the Internationale Brachet Stiftung (IBS); the Walloon Region (“Fonds de Maturation”); The “Amis des Instituts Pasteur à Bruxelles, asbl”.; the University of Brussels (ULB - Action de Recherche Concertée (ARC) grant); and the French INSERM agency “ANRS/Maladies infectieuses émergentes”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This work was primarily supported by the FRS-FNRS Televie grants 30823819 to J-C.T. C.VL., J-C.T. and S.M. are respectively, “Directrice de Recherche”, “Maitre de Recherche” and “Charge de Recherche” of the F.R.S.-FNRS. J-C.T is a visiting research professor at NYUAD. E.P. was a doctoral fellow from the « Télévie » program of the F.R.S.-FNRS and the “Fondation Rose et Jean Hoguet” and next a postdoctoral fellow of Apex Biosolutions (France). S M is further supported by the Funds Suzanne Dechesne, Serge Rousseau and Docteur Jean Gerald, Managed by King Boudouin Foundation. C.M. and S.B. are supported through the Strategic Research Programme (SRP50) of the Vrije Universiteit Brussel. A.S. is supported by a post-doctoral fellowship from the EMBO (ALTF- 709–2021). C.VL. acknowledges funding from the Belgian National Fund for Scientific Research (F.R.S-FNRS, Belgium; grant J.0021.17); the “Télévie” program of the F.R.S.-FNRS; the “Fondation Roi Baudouin”; the Internationale Brachet Stiftung (IBS); the Walloon Region (“Fonds de Maturation”); The “Amis des Instituts Pasteur à Bruxelles, asbl”.; the University of Brussels (ULB - Action de Recherche Concertée (ARC) grant); and the French INSERM agency “ANRS/Maladies infectieuses émergentes”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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