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Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures

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  • Michal S. Barski

    (Section of Virology, Norfolk Place
    Polish Academy of Sciences)

  • Teresa Vanzo

    (Section of Virology, Norfolk Place
    University of Trento)

  • Xue Zhi Zhao

    (National Cancer Institute)

  • Steven J. Smith

    (Centre for Cancer Research, National Cancer Institute)

  • Allison Ballandras-Colas

    (The Francis Crick Institute)

  • Nora B. Cronin

    (The Francis Crick Institute)

  • Valerie E. Pye

    (The Francis Crick Institute)

  • Stephen H. Hughes

    (Centre for Cancer Research, National Cancer Institute)

  • Terrence R. Burke

    (National Cancer Institute)

  • Peter Cherepanov

    (Section of Virology, Norfolk Place
    The Francis Crick Institute)

  • Goedele N. Maertens

    (Section of Virology, Norfolk Place)

Abstract

Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this deltaretrovirus. Here, we screened a library of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffolds to determine their effectiveness in limiting HTLV-1 infection. Naphthyridines with substituents in position 6 emerged as the most potent compounds against HTLV-1, with XZ450 having highest efficacy in vitro. Using single-particle cryo-electron microscopy we visualised XZ450 as well as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the active site of the deltaretroviral intasome. The structures reveal subtle differences in the coordination environment of the Mg2+ ion pair involved in the interaction with the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1 intasome and support their use for pre-exposure prophylaxis and possibly future treatment of HTLV-1 infection.

Suggested Citation

  • Michal S. Barski & Teresa Vanzo & Xue Zhi Zhao & Steven J. Smith & Allison Ballandras-Colas & Nora B. Cronin & Valerie E. Pye & Stephen H. Hughes & Terrence R. Burke & Peter Cherepanov & Goedele N. Ma, 2021. "Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25284-1
    DOI: 10.1038/s41467-021-25284-1
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