Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures.
Amides
Antiviral Agents
/ chemistry
Catalytic Domain
Cryoelectron Microscopy
Deltaretrovirus
Drug Resistance, Viral
/ drug effects
HIV Integrase
/ drug effects
HIV-1
HTLV-I Infections
/ drug therapy
Heterocyclic Compounds, 3-Ring
Human T-lymphotropic virus 1
/ drug effects
Humans
Naphthyridines
/ pharmacology
Piperazines
Pyridones
Recombinant Proteins
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 08 2021
17 08 2021
Historique:
received:
06
04
2021
accepted:
20
07
2021
entrez:
18
8
2021
pubmed:
19
8
2021
medline:
31
8
2021
Statut:
epublish
Résumé
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
Identifiants
pubmed: 34404793
doi: 10.1038/s41467-021-25284-1
pii: 10.1038/s41467-021-25284-1
pmc: PMC8370991
doi:
Substances chimiques
Amides
0
Antiviral Agents
0
Heterocyclic Compounds, 3-Ring
0
Naphthyridines
0
Piperazines
0
Pyridones
0
Recombinant Proteins
0
bictegravir
8GB79LOJ07
HIV Integrase
EC 2.7.7.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4996Subventions
Organisme : Wellcome Trust
ID : 107005/Z/15Z
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : FC001061
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : P50 AI150481
Pays : United States
Organisme : Wellcome Trust
ID : FC001061
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
ID : FC001061
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 206175/Z/17/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : FC001061
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2021. The Author(s).
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