Dolutegravir (S/GSK1349572) Exhibits Significantly Slower Dissociation than Raltegravir and Elvitegravir from Wild-Type and Integrase Inhibitor-Resistant HIV-1 Integrase-DNA Complexes

Hightower, Kendra E.; Wang, Ruolan; Deanda, Felix; Johns, Brian A.; Weaver, K.; Shen, Yongping; Tomberlin, Ginger H.; Carter, H. Luke; Broderick, Timothy M; Scott, Stuart A.; Seki, Takahiro; Kobayashi, Masanori; Underwood, Mark

doi:10.1128/aac.00157-11

Cited by 205 publications

(207 citation statements)

References 38 publications

(47 reference statements)

Supporting

Mentioning

195

Contrasting

Unclassified

Order By: Relevance

“…Instead, the substitutions appear to subtly affect local active site geometry, such that binding of the drug to mutant enzymes requires significant energetically unfavorable rearrangement of the IN CCD (68). Consistent with this interpretation, resistance changes correlate with significant increases in drug dissociation rates from these enzymes (71). The PIC harbors a unique enzymatic antiviral target: formed through IN processing of the LTR ends in the cytoplasm, the functional CDC must persist for sufficient time to accommodate PIC nuclear import, chromatin targeting, and IN strand transfer activity (Fig.…”

Section: In Strand Transfer Inhibitorssupporting

confidence: 59%

“…Co-crystallization with the PFV CDC revealed an extended linker region between the metal-binding heteroatoms and the halobenzyl arm that allowed the drug to intimately contact the viral LTR end and IN ␤4-␣2 loop region (Fig. 3B) (69), likely contributing to the slower dissociation of DTG versus RAL from HIV-1 IN-LTR complexes in vitro (71). The relative difficulty in selecting for DTG-resistant viruses ex vivo (47) suggests that the generation of resistance in vivo might occur less frequently than what has been seen with RAL.…”

Section: In Strand Transfer Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Retroviral Integrase Proteins and HIV-1 DNA Integration

Krishnan

Engelman

2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Retroviral integrases catalyze two reactions, 3-processing of viral DNA ends, followed by integration of the processed ends into chromosomal DNA. X-ray crystal structures of integrase-DNA complexes from prototype foamy virus, a member of the Spumavirus genus of Retroviridae, have revealed the structural basis of integration and how clinically relevant integrase strand transfer inhibitors work. Underscoring the translational potential of targeting virus-host interactions, small molecules that bind at the host factor lens epithelium-derived growth factor/ p75-binding site on HIV-1 integrase promote dimerization and inhibit integrase-viral DNA assembly and catalysis. Here, we review recent advances in our knowledge of HIV-1 DNA integration, as well as future research directions.Retroviral replication proceeds through an obligate proviral or integrated DNA recombination intermediate. Integration provides a favorable environment for efficient gene expression, ensures inheritance of the virus in both daughter cells during mitosis, and forms the basis for latent HIV-1 reservoirs that persist in the face of highly active antiretroviral therapy. The early events of retroviral replication take place within the context of nucleoprotein complexes that are derived from the core of the infecting virus particle (1, 2). Within the confines of the reverse transcription complex (RTC), 2 the reverse transcriptase enzyme copies single-stranded viral RNA into a linear double-stranded DNA molecule containing a copy of the LTR sequence at each end. The viral integrase (IN) engages the LTR ends prior to catalyzing two spatially and temporally distinct chemical reactions. Soon after their synthesis (3), IN site-specifically processes each LTR end adjacent to an invariant CA dinucleotide (4, 5), yielding CA OH 3Ј-hydroxyl groups that serve as the nucleophiles for the second reaction, DNA strand transfer. Because the viral replication intermediate at this point gains the ability to catalyze DNA strand transfer activity, 3Ј-processing operationally marks the transition of the RTC to the pre-integration complex (PIC) (Fig. 1). In the strand transfer step, IN utilizes the 3Ј-oxygen atoms to cut chromosomal DNA in a staggered fashion and simultaneously join the viral DNA ends to the 5Ј-phosphates of the target DNA (4, 6, 7). The resulting DNA recombination intermediate, with unjoined viral DNA 5Ј-ends, is repaired by host cell enzymes to yield the integrated provirus flanked by the duplication of the sequence of the staggered DNA cut (Fig. 1). The spumaviruses, which compose one of seven Retroviridae genera, are an exception to this generalized scheme, as DNA synthesis is largely complete prior to target cell infection (8). Research on the functionality of the active nucleoprotein complexes that mediate HIV-1 DNA integration has led to the development of antiviral inhibitors that target the IN and block integration. IN Domain Structure and Reaction MechanismRetroviral INs belong to a superfamily of proteins known as the retroviral IN superfam...

show abstract

Section: In Strand Transfer Inhibitorssupporting

confidence: 59%

Section: In Strand Transfer Inhibitorsmentioning

confidence: 99%

Retroviral Integrase Proteins and HIV-1 DNA Integration

Krishnan

Engelman

2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Interestingly, no additional compensatory mutations have been identified for DTG, even in cell culture selection experiments conducted over more than 4 years (Wainberg and Han 2015). It is generally believed that the higher genetic barrier of DTG to resistance of HIV-1 is due to its slow dissociation rate from integrase-DNA complexes, in comparison with RAL and EVG (Hightower et al 2011;Geretti et al 2012;Osman et al 2015;Wainberg and Han 2015). Some studies have shown that DTG has an extended linker that allows its difluorophenyl group to enter farther into the pocket within the integrase active site, compared with other INSTIs, and that DTG has the ability to adjust its structure and conformation in response to structural changes within the active sites of RAL-and EVG-resistant integrases, compared with RAL and EVG ( Fig.…”

Section: >100 Nd <50mentioning

confidence: 99%

Might dolutegravir be part of a functional cure for HIV?

2016

View full text Add to dashboard Cite

Antiretroviral therapy (ART) has greatly decreased HIV-related morbidity and mortality. However, HIV can establish viral reservoirs that evade both the immune system and ART. Dolutegravir (DTG) is a secondgeneration integrase strand transfer inhibitor (INSTI) related to the first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG). DTG shows a higher genetic barrier to the development of HIV-1 resistance than RAL and EVG. More interestingly, clinical resistance mutations to DTG in treatment-naïve patients have not been observed to date. This review summarizes recent studies on strategies toward a cure for HIV, explores resistance profiles of DTG, and discusses how DTG might help in finding a functional cure for HIV.Key words: dolutegravir, drug resistance, HIV, cure. Résumé :Les traitements antirétroviraux (TAR) ont considérablement réduit la morbidité et la mortalité associées au VIH. Or, le VIH peut établir des réservoirs viraux pour se soustraire au système immunitaire et aux TAR. Le dolutégravir (DTG) est un inhibiteur du transfert de brin par l'intégrase (integrase strand transfer inhibitor, INSTI) de deuxième génération qui s'apparente au raltégravir (RAL) et à l'elvitégravir (EVG), des INSTI de première génération. Comparativement au RAL et à l'EVG, le DTG présente une plus grande barrière génétique au dével-oppement de la résistance chez le VIH. On remarque avec intérêt que des mutations menant à la résistance clinique au DTG chez des patients jamais traités auparavant n'ont pas encore été observées. La présente revue fait la synthèse des études récentes abordant des stratégies visant à éliminer le VIH, explore les profils de résistance au DTG et discute de la possibilité de mettre au point un remède contre le VIH à l'aide du DTG. [Traduit par la Rédaction]

show abstract

“…An in vitro study demonstrated that the highest genetic barrier of DTG may be attributed to its significantly slower rate of dissociation from the integrase enzyme in viruses that are either wildtype or contain the N155, Q148 or Y143 mutations [Hightower et al 2011]. Furthermore, DTG may undergo slight conformational change at the active site to overcome the physical barrier created by these single point mutations [Hare et al 2011].…”

Section: Insti Resistance Patternmentioning

confidence: 99%

Dolutegravir: clinical efficacy and role in HIV therapy

Fantauzzi

Mezzaroma

2014

Therapeutic Advances in Chronic Disease

View full text Add to dashboard Cite

Abstract:The human immunodeficiency virus type-1 (HIV-1) integrase enzyme has recently emerged as a primary alternative target to block viral replication, and integrase strand transfer inhibitors (INSTIs) are now considered an alternative 'third agent' class of antiretroviral (ARV) drugs. Dolutegravir is the first next-generation INSTI showing some novel and intriguing characteristics: it has a favorable pharmacokinetic profile with a prolonged intracellular halflife, rendering feasible a once daily dosing without the need for pharmacokinetic boosting. Secondly, it is largely metabolized via uridine diphosphate glucuronosyltransferase-1A1 with a minor component of cytochrome P450 isoforms, thus allowing a low grade of drug-drug interactions, so that its metabolic profile consents coadministration with the majority of the other ARV drugs without dose adjustments. Lastly, but no less important, virological studies have clearly demonstrated that dolutegravir has a significant activity against HIV-1 isolates showing raltegravir and/or elvitegravir associated resistance mutations. The attributes of once daily administration and the potential to treat INSTI-resistant viruses make dolutegravir an interesting and promising new agent in the treatment of both naïve and experienced HIV-1 subjects. In this review, the main concerns on dolutegravir efficacy are focused through the analysis of the currently available data from clinical studies in naïve and experienced patients, evaluating its possible place within the anti-HIV-1 drug armamentarium. The development of newer once daily, single tablet coformulations improved drug adherence and maximized the success of ARV therapy. Pharmacokinetic studies and dose-ranging trials suggested that dolutegravir is a good candidate for a single tablet regimen in one or more new coformulated pills that will be available in the near future.

show abstract

Dolutegravir (S/GSK1349572) Exhibits Significantly Slower Dissociation than Raltegravir and Elvitegravir from Wild-Type and Integrase Inhibitor-Resistant HIV-1 Integrase-DNA Complexes

Abstract: The integrase inhibitor (INI) dolutegravir (DTG; S/GSK1349572

Cited by 205 publications

References 38 publications

Retroviral Integrase Proteins and HIV-1 DNA Integration

Retroviral Integrase Proteins and HIV-1 DNA Integration

Might dolutegravir be part of a functional cure for HIV?

Dolutegravir: clinical efficacy and role in HIV therapy

Contact Info

Product

Resources

About