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

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) candidat...

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Veröffentlicht in:Nature communications Jg. 12; H. 1; S. 4996 - 10
Hauptverfasser: Barski, Michal S., Vanzo, Teresa, Zhao, Xue Zhi, Smith, Steven J., Ballandras-Colas, Allison, Cronin, Nora B., Pye, Valerie E., Hughes, Stephen H., Burke, Terrence R., Cherepanov, Peter, Maertens, Goedele N.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 17.08.2021
Nature Publishing Group
Nature Portfolio
Schlagworte:
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Amides
Antiretroviral drugs
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Binding
Catalytic Domain
Cryoelectron Microscopy
Deltaretrovirus
Disease prevention
Drug Resistance, Viral - drug effects
Electron microscopy
Heterocyclic Compounds, 3-Ring
HIV
HIV Integrase - drug effects
HIV-1
HTLV-I Infections - drug therapy
Human immunodeficiency virus
Human T-lymphotropic virus 1 - drug effects
Human T-lymphotropic virus 1 - genetics
Humanities and Social Sciences
Humans
Infections
Inhibitors
Integrase
Ion pairs
Life Sciences
Lymphocytes T
Magnesium
multidisciplinary
Naphthyridines - pharmacology
Piperazines
Prophylaxis
Pyridones
Recombinant Proteins
Science
Science (multidisciplinary)
Structural analysis
Viruses
ISSN:2041-1723, 2041-1723
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Zusammenfassung: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. Human T-cell lymphotropic virus type 1 (HTLV-1) is an oncogenic deltaretrovirus. Here the authors provide structural characterization of the binding mechanism of novel integrase strand transfer inhibitor (INSTI) candidates to limit HTLV-1 infection.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-25284-1