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Structure of the STLV intasome:B56 complex bound to the strand-transfer inhibitor bictegravirStructure of the STLV intasome:B56 complex bound to the strand-transfer inhibitor bictegravir
Structural highlights
FunctionPublication Abstract from PubMedBetween 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. Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures.,Barski MS, Vanzo T, Zhao XZ, Smith SJ, Ballandras-Colas A, Cronin NB, Pye VE, Hughes SH, Burke TR Jr, Cherepanov P, Maertens GN Nat Commun. 2021 Aug 17;12(1):4996. doi: 10.1038/s41467-021-25284-1. PMID:34404793[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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