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Differential screening identifies molecules specifically inhibiting CCR5 transport to the cell surface and HIV infection

Gaelle Boncompain, Floriane Herit, Sarah Tessier, Aurianne Lescure, Elaine Del Nery, Pierre Gestraud, Isabelle Staropoli, Yuko Fukata, Masaki Fukata, Anne Brelot, Florence Niedergang, View ORCID ProfileFranck Perez
doi: https://doi.org/10.1101/364927
Gaelle Boncompain
1Institut Curie, PSL Research University, CNRS UMR144, F-75005, Paris, France
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  • For correspondence: gaelle.boncompain@curie.fr franck.perez@curie.fr
Floriane Herit
2Inserm, U1016, Institut Cochin, F-75014, Paris, France
3CNRS, UMR 8104, F-75014, Paris, France
4Université Paris Descartes, Sorbonne Paris Cité, F-75014, Paris, France
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Sarah Tessier
5Institut Curie, PSL Research University, Translational Department, F-75005 Paris, France
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Aurianne Lescure
5Institut Curie, PSL Research University, Translational Department, F-75005 Paris, France
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Elaine Del Nery
5Institut Curie, PSL Research University, Translational Department, F-75005 Paris, France
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Pierre Gestraud
6Institut Curie, PSL Research University, Bioinformatics facility, INSERM U900, F-75005 Paris, France
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Isabelle Staropoli
7Inserm U1108, Viral pathogenesis unit, Department of Virology, Institut Pasteur, F-75015, Paris, France
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Yuko Fukata
8Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan
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Masaki Fukata
8Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan
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Anne Brelot
7Inserm U1108, Viral pathogenesis unit, Department of Virology, Institut Pasteur, F-75015, Paris, France
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Florence Niedergang
2Inserm, U1016, Institut Cochin, F-75014, Paris, France
3CNRS, UMR 8104, F-75014, Paris, France
4Université Paris Descartes, Sorbonne Paris Cité, F-75014, Paris, France
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Franck Perez
1Institut Curie, PSL Research University, CNRS UMR144, F-75005, Paris, France
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  • ORCID record for Franck Perez
  • For correspondence: gaelle.boncompain@curie.fr franck.perez@curie.fr
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Abstract

Proteins destined to the cell surface are conveyed through membrane-bound compartments using the secretory pathway. Multiple secretory routes exist in cells, which paves the way to the development of inhibitory molecules able to specifically perturb the transport of a chosen cargo. We used differential high-content screening of chemical libraries to identify molecules reducing the secretion of CCR5, the major co-receptor for HIV-1 entry. Three molecules strongly affected the anterograde transport of CCR5, without inhibiting the transport of the related G protein-coupled receptors CCR1 and CXCR4. These three molecules perturb the transport of endogenous CCR5 and decrease the entry of HIV in human primary target cells. Two molecules were found to share the same mode of action, inhibiting palmitoylation of CCR5. Our results demonstrate that secretory routes can be specifically targeted which allows to envisage novel strategies to provoke the intracellular retention or rerouting of secretory proteins involved in disease development.

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Posted July 08, 2018.
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Differential screening identifies molecules specifically inhibiting CCR5 transport to the cell surface and HIV infection
Gaelle Boncompain, Floriane Herit, Sarah Tessier, Aurianne Lescure, Elaine Del Nery, Pierre Gestraud, Isabelle Staropoli, Yuko Fukata, Masaki Fukata, Anne Brelot, Florence Niedergang, Franck Perez
bioRxiv 364927; doi: https://doi.org/10.1101/364927
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Differential screening identifies molecules specifically inhibiting CCR5 transport to the cell surface and HIV infection
Gaelle Boncompain, Floriane Herit, Sarah Tessier, Aurianne Lescure, Elaine Del Nery, Pierre Gestraud, Isabelle Staropoli, Yuko Fukata, Masaki Fukata, Anne Brelot, Florence Niedergang, Franck Perez
bioRxiv 364927; doi: https://doi.org/10.1101/364927

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