Article Dans Une Revue Nature Communications Année : 2021

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

Michal Barski
Teresa Vanzo
Xue Zhi Zhao
Steven Smith
Valerie Pye
Stephen Hughes
Terrence Burke
Peter Cherepanov
Goedele Maertens

Résumé

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 Mg 2+ 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.

Dates et versions

hal-04246068 , version 1 (17-10-2023)

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Citer

Michal Barski, Teresa Vanzo, Xue Zhi Zhao, Steven Smith, Allison Ballandras-Colas, et al.. Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures. Nature Communications, 2021, 12 (1), pp.4996. ⟨10.1038/s41467-021-25284-1⟩. ⟨hal-04246068⟩

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