Structural and Functional Analyses of the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir (S/GSK1349572)
Open accessAbstract
Raltegravir (RAL) and related HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) efficiently block viral replication in vitro and suppress viremia in patients. These small molecules bind to the IN active site, causing it to disengage from the deoxyadenosine at the 3' end of viral DNA. The emergence of viral strains that are highly resistant to RAL underscores the pressing need to develop INSTIs with improved resistance profiles. Herein, we show that the candidate second-generation drug dolutegravir (DTG, S/GSK1349572) effectively inhibits a panel of HIV-1 IN variants resistant to first-generation INSTIs. To elucidate the structural basis for the increased potency of DTG against RAL-resistant INs, we determined crystal structures of wild-type and mutant prototype foamy virus intasomes bound to this compound. The overall IN binding mode of DTG is strikingly similar to that of the tricyclic hydroxypyrrole MK-2048. Both second-generation INSTIs occupy almost the same physical space within the IN active site and make contacts with the β4-α2 loop of the catalytic core domain. The extended linker region connecting the metal chelating core and the halobenzyl group of DTG allows it to enter farther into the pocket vacated by the displaced viral DNA base and to make more intimate contacts with viral DNA, compared with those made by RAL and other INSTIs. In addition, our structures suggest that DTG has the ability to subtly readjust its position and conformation in response to structural changes in the active sites of RAL-resistant INs.
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Second-generation INSTIs have extended scaffolds that fill the active site more completely and make additional interactions with the integrase backbone.
“The second-generation compounds feature extended scaffolds, allowing them to fill the active site more completely, and make additional interactions with the IN backbone35,36,162.”
From Structure and function of retroviral integrase (2022) · cites this paper as [162]
The crystal-structure section (p. 567) says second-generation INSTIs extend toward an integrase residue, and the Discussion (p. 570) says dolutegravir’s extended linker lets it reach deeper into the active-site pocket and make closer contacts than raltegravir. The paper describes contacts with an integrase loop, but does not establish the claimed additional interactions specifically with the integrase backbone. (LLM, conf=0.85)
Experimental — accuracy not yet measuredINSTI mode of action was visualized in PFV intasome crystals and refined in HIV-1 and SIV cryo-EM structures.
“The mode of action of these compounds was visualized in crystals of the PFV intasome25,161,162 and later refined in HIV-1 and SIV cryo-EM structures35,36.”
From Structure and function of retroviral integrase (2022) · cites this paper as [162]
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References 38 · Cited by 264
Research works printed but not linked: 4
- Engelman A (2010) Reverse transcription and integration, in Retroviruses: Molecu- lar Biology, Genomics and Pathogenesis (Kurth R and Bannert N eds) pp 129 -159, Caister Academic Press, Norfolk, United Kingdom.
- Johns B, Kawasuiji T, Taishi T, Yoshida H, Garvey E, Spreen W, Underwood M, Sato A, Yoshinaga T and Fujiwara T (2010) The discovery of S/GSK1349572: a once- daily next generation integrase inhibitor with a superior resistance profile, in 17th Conference on Retroviruses and Opportunistic Infections, 2010 Feb 16 -19, San Francisco, CA. Conference on Retroviruses and Opportunistic Infections, Alexan- dria, VA.
- Seki T, Kobayashi M, Wakasa-Morimoto C, Yoshinaga T, Sato A, Fujiwara T, Underwood M, Garvey E and Johns B (2010) S/GSK1349572 is a potent next generation HIV integrase inhibitor and demonstrates a superior resistance profile substantiated with 60 integrase mutant molecular clones, in 17th Conference on Retroviruses and Opportunistic Infections, 2010 Feb 16 -19, San Francisco, CA. Conference on Retroviruses and Opportunistic Infections, Alexandria, VA. Structural and Functional Analyses of Dolutegravir
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- Authors
- Hare, S., Smith, S. J., Métifiot, M., Jaxa-Chamiec, A., Pommier, Y., Hughes, S. H., & Cherepanov, P.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Cherepanov, Peter
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2011-10
- Volume
- 80
- Issue
- 4
- Pages
- 565-572
- ISSN
- 0026-895X (ISSN-L)
- PMC
- PMC3187526
- OpenAlex
- W2149150781
- Cited by
- 264
- References
- 38
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 14 · 2023: 7 · 2022: 8 · 2021: 20 · 2020: 16 · 2019: 16 · 2018: 15 · 2017: 17 · 2016: 19 · 2015: 26 · 2014: 36 · 2013: 20 · 2012: 26
- FWCI
- 19.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Wellcome Trust
- Diamond Light Source
- National Institutes of Health
- Medical Research Council (G1000917)
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- dolutegravir, HIV-1 integrase, integrase strand transfer inhibitors, raltegravir resistance, viral DNA binding, drug resistance, antiretroviral drug design
- MeSH terms
- Dolutegravir, Binding Sites, Heterocyclic Compounds, 3-Ring, Humans, Oxazines, Piperazines, Pyridones, Structure-Activity Relationship, Tumor Cells, Cultured, Genetic Variation, Crystallography, X-Ray, HIV Integrase, HIV Integrase Inhibitors, HEK293 Cells
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