Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures
File(s)
Published version
Author(s)
Type
Journal Article
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.
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 Issued
2021-08-17
Date Acceptance
2021-07-20
Citation
Nature Communications, 2021, 12 (4996), pp.1-10
ISSN
2041-1723
Publisher
Nature Research
Start Page
1
End Page
10
Journal / Book Title
Nature Communications
Volume
12
Issue
4996
Copyright Statement
© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Sponsor
Wellcome Trust
Identifier
https://www.nature.com/articles/s41467-021-25284-1
Grant Number
107005/Z/15/Z
Publication Status
Published
Date Publish Online
2021-08-17