s41467-021-25284-1 (1).pdf (1.85 MB)

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

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journal contribution
posted on 26.08.2021, 12:54 by 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 Maertens
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.

Funding

Crick (Grant ID: 10061, Grant title: Cherepanov FC001061) Crick (Grant ID: 10015, Grant title: STP Structural Biology)

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