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Structural basis of second-generation HIV integrase inhibitor action and viral resistance

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Structural basis of second-generation HIV integrase inhibitor action and viral resistance. / Cook, Nicola J.; Li, Wen; Berta, Dénes; Badaoui, Magd; Ballandras-colas, Allison; Nans, Andrea; Kotecha, Abhay; Rosta, Edina; Engelman, Alan N.; Cherepanov, Peter.

In: Science, Vol. 367, No. 6479, 14.02.2020, p. 806-810.

Research output: Contribution to journalArticle

Harvard

Cook, NJ, Li, W, Berta, D, Badaoui, M, Ballandras-colas, A, Nans, A, Kotecha, A, Rosta, E, Engelman, AN & Cherepanov, P 2020, 'Structural basis of second-generation HIV integrase inhibitor action and viral resistance', Science, vol. 367, no. 6479, pp. 806-810. https://doi.org/10.1126/science.aay4919

APA

Cook, N. J., Li, W., Berta, D., Badaoui, M., Ballandras-colas, A., Nans, A., Kotecha, A., Rosta, E., Engelman, A. N., & Cherepanov, P. (2020). Structural basis of second-generation HIV integrase inhibitor action and viral resistance. Science, 367(6479), 806-810. https://doi.org/10.1126/science.aay4919

Vancouver

Cook NJ, Li W, Berta D, Badaoui M, Ballandras-colas A, Nans A et al. Structural basis of second-generation HIV integrase inhibitor action and viral resistance. Science. 2020 Feb 14;367(6479):806-810. https://doi.org/10.1126/science.aay4919

Author

Cook, Nicola J. ; Li, Wen ; Berta, Dénes ; Badaoui, Magd ; Ballandras-colas, Allison ; Nans, Andrea ; Kotecha, Abhay ; Rosta, Edina ; Engelman, Alan N. ; Cherepanov, Peter. / Structural basis of second-generation HIV integrase inhibitor action and viral resistance. In: Science. 2020 ; Vol. 367, No. 6479. pp. 806-810.

Bibtex Download

@article{c676b8e61be84904aa2d5130bd15905b,
title = "Structural basis of second-generation HIV integrase inhibitor action and viral resistance",
abstract = "Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics.",
author = "Cook, {Nicola J.} and Wen Li and D{\'e}nes Berta and Magd Badaoui and Allison Ballandras-colas and Andrea Nans and Abhay Kotecha and Edina Rosta and Engelman, {Alan N.} and Peter Cherepanov",
year = "2020",
month = feb,
day = "14",
doi = "10.1126/science.aay4919",
language = "English",
volume = "367",
pages = "806--810",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6479",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Structural basis of second-generation HIV integrase inhibitor action and viral resistance

AU - Cook, Nicola J.

AU - Li, Wen

AU - Berta, Dénes

AU - Badaoui, Magd

AU - Ballandras-colas, Allison

AU - Nans, Andrea

AU - Kotecha, Abhay

AU - Rosta, Edina

AU - Engelman, Alan N.

AU - Cherepanov, Peter

PY - 2020/2/14

Y1 - 2020/2/14

N2 - Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics.

AB - Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics.

UR - http://www.scopus.com/inward/record.url?scp=85079288973&partnerID=8YFLogxK

U2 - 10.1126/science.aay4919

DO - 10.1126/science.aay4919

M3 - Article

VL - 367

SP - 806

EP - 810

JO - Science

JF - Science

SN - 0036-8075

IS - 6479

ER -

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