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Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics.

ABSTRACT: Signature HIV-1 integrase mutations associated with clinical raltegravir resistance involve 1 of 3 primary genetic pathways, Y143C/R, Q148H/K/R and N155H, the latter 2 of which confer cross-resistance to elvitegravir. In accord with clinical findings, in vitro drug resistance profiling studies with wild-type and site-directed integrase mutant viruses have shown significant fold increases in raltegravir and elvitegravir resistance for the specified viral mutants relative to wild-type HIV-1. Dolutegravir, in contrast, has demonstrated clinical efficacy in subjects failing raltegravir therapy due to integrase mutations at Y143, Q148 or N155, which is consistent with its distinct in vitro resistance profile as dolutegravir's antiviral activity against these viral mutants is equivalent to its activity against wild-type HIV-1. Kinetic studies of inhibitor dissociation from wild-type and mutant integrase-viral DNA complexes have shown that dolutegravir also has a distinct off-rate profile with dissociative half-lives substantially longer than those of raltegravir and elvitegravir, suggesting that dolutegravir's prolonged binding may be an important contributing factor to its distinct resistance profile. To provide a structural rationale for these observations, we constructed several molecular models of wild-type and clinically relevant mutant HIV-1 integrase enzymes in complex with viral DNA and dolutegravir, raltegravir or elvitegravir. Here, we discuss our structural models and the posited effects that the integrase mutations and the structural and electronic properties of the integrase inhibitors may have on the catalytic pocket and inhibitor binding and, consequently, on antiviral potency in vitro and in the clinic.

SUBMITTER: DeAnda F

PROVIDER: S-EPMC3797783 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics.

DeAnda Felix F Hightower Kendra E KE Nolte Robert T RT Hattori Kazunari K Yoshinaga Tomokazu T Kawasuji Takashi T Underwood Mark R MR

PloS one 20131016 10

Signature HIV-1 integrase mutations associated with clinical raltegravir resistance involve 1 of 3 primary genetic pathways, Y143C/R, Q148H/K/R and N155H, the latter 2 of which confer cross-resistance to elvitegravir. In accord with clinical findings, in vitro drug resistance profiling studies with wild-type and site-directed integrase mutant viruses have shown significant fold increases in raltegravir and elvitegravir resistance for the specified viral mutants relative to wild-type HIV-1. Dolut ...[more]

PMID: 24146996

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Project description:Resistance associated mutations (RAMs) threaten the long-term success of combination antiretroviral therapy (cART) outcomes for HIV-1 treatment. HIV-1 Integrase (IN) strand transfer inhibitors (INSTIs) have proven to be a viable option for highly specific HIV-1 therapy. The INSTI, Dolutegravir is recommended by the World Health Organization for use as first-line cART. This study aims to understand how RAMs affect the stability of IN, as well as the binding of the drug Dolutegravir to the catalytic pocket of the protein. A homology model of HIV-1 subtype C IN was successfully constructed and validated. The site directed mutator webserver was used to predict destabilizing and/or stabilizing effects of known RAMs while FoldX confirmed any changes in protein energy upon introduction of mutation. Also, interaction analysis was performed between neighbouring residues. Three mutations known to be associated with Raltegravir, Elvitegravir and Dolutegravir resistance were selected; E92Q, G140S and Y143R, for molecular dynamics simulations. The structural quality assessment indicated high reliability of the HIV-1C IN tetrameric structure, with more than 90% confidence in modelled regions. Change in free energy for the three mutants indicated different effects, while simulation analysis showed G140S to have the largest affect on protein stability and flexibility. This was further supported by weaker non-bonded pairwise interaction energy and binding free energy values between the drug DTG and E92Q, Y143R and G140S mutants suggesting reduced binding affinity, as indicated by interaction analysis in comparison to the WT. Our findings suggest the G140S mutant has the strongest effect on the HIV-1C IN protein structure and Dolutegravir binding. To the best of our knowledge, this is the first study that uses the consensus wild type HIV-1C IN sequence to build an accurate 3D model to understand the effect of three known mutations on DTG drug binding in a South Africa context.

Project description:Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI) currently under review by the US Food and Drug Administration for marketing approval. The in vitro, protein-adjusted 90 % inhibitory concentration (IC90) of dolutegravir for wild-type virus is 0.064 ?g/ml, and it retains in vitro anti-HIV 1 activity across a broad range of viral phenotypes that are known to confer resistance to the currently marketed INSTIs, raltegravir and elvitegravir. Dolutegravir has a terminal elimination half-life of 13-14 h and maintains concentrations over the in vitro, protein-adjusted IC90 for more than 30 h following a single dose. Additionally, dolutegravir has low inter-subject variability compared with raltegravir and elvitegravir. A plasma exposure-response relationship has been well described, with antiviral activity strongly correlating with trough concentrations. Phase III trials have assessed the antiviral activity of dolutegravir compared with efavirenz and raltegravir in antiretroviral (ARV)-naive patients and found that dolutegravir achieved more rapid and sustained virologic suppression in both instances. Additionally, studies of dolutegravir activity in patients with known INSTI-resistant mutations have been favourable, indicating that dolutegravir retains activity in a variety of INSTI-resistant phenotypes. Much like currently marketed INSTIs, dolutegravir is very well tolerated. Because dolutegravir inhibits the renal transporter organic cation transporter 2, reduced tubular secretion of creatinine leads to non-progressive increases in serum creatinine. These serum creatinine increases have not been associated with a decreased glomerular filtration rate or progressive renal impairment. Dolutegravir's major and minor metabolic pathways are uridine diphosphate glucuronosyltransferase 1A1 and cytochrome P450 (CYP)-3A4, respectively, and it neither induces nor inhibits CYP isoenzymes. Thus dolutegravir has a modest drug interaction profile. However, antacids significantly decrease dolutegravir plasma exposure and should be separated by 2 h before, or 6 h after, a dolutegravir dose. In summary, dolutegravir is the first of the second-generation INSTIs and exhibits a predictable pharmacokinetic profile and a well-defined exposure-response relationship. Dolutegravir retains activity despite the presence of some class-resistant mutations and achieves rapid and sustained virologic suppression in ARV-naive and ARV-experienced patients. Clinically, dolutegravir is poised to become a commonly used component of antiretroviral regimens.

Dataset Information

Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics.

Publications

Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics.

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