Imperial College London
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Professor Peter Cherepanov

Faculty of Medicine, Department of Infectious Disease

Professor of Molecular Virology
 
 
 
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Contact

 

p.cherepanov

 
 
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Location

 

Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Citation

BibTex format

@article{Cook:2020:10.1126/science.aay4919,
author = {Cook, NJ and Li, W and Berta, D and Badaoui, M and Ballandras-Colas, A and Nans, A and Kotecha, A and Rosta, E and Engelman, AN and Cherepanov, P},
doi = {10.1126/science.aay4919},
journal = {Science},
pages = {806--810},
title = {Structural basis of second-generation HIV integrase inhibitor action and viral resistance},
url = {http://dx.doi.org/10.1126/science.aay4919},
volume = {367},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Despite worldwide prescription, the mechanistic basis for superiority of second-generation HIV integrase (IN) strand transfer inhibitors (INSTIs) is poorly understood. We use single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near atomic resolution. Q148H/G140S amino acid substitutions in IN that pervade 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, which are critical for antagonizing Q148H/G140S mutant virus. 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 important class of anti-HIV/AIDS therapeutics.
AU  - Cook,NJ
AU  - Li,W
AU  - Berta,D
AU  - Badaoui,M
AU  - Ballandras-Colas,A
AU  - Nans,A
AU  - Kotecha,A
AU  - Rosta,E
AU  - Engelman,AN
AU  - Cherepanov,P
DO  - 10.1126/science.aay4919
EP  - 810
PY  - 2020///
SN  - 0036-8075
SP  - 806
TI  - Structural basis of second-generation HIV integrase inhibitor action and viral resistance
T2  - Science
UR  - http://dx.doi.org/10.1126/science.aay4919
UR  - https://science.sciencemag.org/content/early/2020/01/30/science.aay4919
UR  - http://hdl.handle.net/10044/1/76563
VL  - 367
ER  -
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