Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures
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 and
Goedele N. Maertens ()
Additional contact information
Michal S. Barski: Section of Virology, Norfolk Place
Teresa Vanzo: Section of Virology, Norfolk Place
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
Goedele N. Maertens: Section of Virology, Norfolk Place
Nature Communications, 2021, vol. 12, issue 1, 1-10
Abstract:
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.
Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25284-1
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DOI: 10.1038/s41467-021-25284-1
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