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HIV-1 integrase inhibitor T30177 forms a stacked dimeric G-quadruplex structure containing bulges.

ABSTRACT: T30177 is a G-rich oligonucleotide with the sequence (GTGGTGGGTGGGTGGGT) which inhibits the HIV-1 integrase activity at nanomolar concentrations. Here we show that this DNA sequence forms in K(+) solution a dimeric G-quadruplex structure comprising a total of six G-tetrad layers through the stacking of two propeller-type parallel-stranded G-quadruplex subunits at their 5'-end. All twelve guanines in the sequence participate in the G-tetrad formation, despite the interruption in the first G-tract by a thymine, which forms a bulge between two adjacent G-tetrads. In this work, we also propose a simple analytical approach to stoichiometry determination using concentration-dependent melting curves.

SUBMITTER: Mukundan VT

PROVIDER: S-EPMC3203613 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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HIV-1 integrase inhibitor T30177 forms a stacked dimeric G-quadruplex structure containing bulges.

Mukundan Vineeth Thachappilly VT Do Ngoc Quang NQ Phan Anh Tuân AT

Nucleic acids research 20110719 20

T30177 is a G-rich oligonucleotide with the sequence (GTGGTGGGTGGGTGGGT) which inhibits the HIV-1 integrase activity at nanomolar concentrations. Here we show that this DNA sequence forms in K(+) solution a dimeric G-quadruplex structure comprising a total of six G-tetrad layers through the stacking of two propeller-type parallel-stranded G-quadruplex subunits at their 5'-end. All twelve guanines in the sequence participate in the G-tetrad formation, despite the interruption in the first G-tract ...[more]

PMID: 21771859

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Project description:BackgroundIntegrase inhibitors (INI) induce a rapid decline of HIV-RNA in plasma and CD4+ T-cell recovery in blood. Both characteristics are also associated with immune reconstitution inflammatory syndrome (IRIS). Whether the use of INI-containing combination antiretroviral therapy (cART) increases the risk of IRIS is being questioned.MethodsStudy within the Dutch ATHENA HIV observational cohort. HIV-1 infected late presenters initiating cART after March 2009 were included if they had <200 CD4+ T-cells per μL and were diagnosed with an opportunistic infection. IRIS was defined either according to the criteria by French et al. (IRISFRENCH) or by a clinical IRIS diagnosis of the physician (IRISCLINICAL). The primary outcomes were the association between INI and the occurrence of IRISFRENCH and IRISFRENCH+CLINICAL in multivariable logistic regression.Findings672 patients with a median CD4+ T-cell count of 35 cells per μL were included. Treatment with INI was independently associated with IRISFRENCH as well as IRISFRENCH+CLINICAL (OR 2·43, 95%CI:1·45-4·07, and OR 2·17, 95%CI:1·45-3·25). When investigating INI separately, raltegravir (RAL) remained significantly associated with IRISFRENCH (OR 4·04 (95%CI:1·99-8·19) as well as IRISFRENCH+CLINICAL (OR 3·07, 95%CI:1·66-5·69), while dolutegravir (DTG) became associated with IRISFRENCH+CLINICAL after it replaced RAL as preferred INI in the cohort after 2015 (OR 4·08, 95%CI:0·99-16·82, p=0·052). Too few patients used elvitegravir to draw meaningful conclusions. Steroid initiation for IRIS was more likely in those who initiated INI versus in those who did not, but no increased hospital (re)admission or mortality rates were observed.InterpretationIn HIV late presenters from a resource rich setting, INI based treatment initiation increased the risk of IRIS. This was observed for RAL and DTG when being initiated as preferential INI in the presence of specific AIDS-conditions, indicative of channeling bias. Although we controlled for all relevant measured confounders, we cannot exclude that the observed association is partially explained by residual confounding. INI use was not associated with mortality nor hospitalization. Therefore, our observation is no reason to avoid INI in late presenters.FundingThe ATHENA database is maintained by Stichting HIV Monitoring and supported by a grant from the Dutch Ministry of Health, Welfare and Sport through the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment.

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HIV-1 integrase inhibitor T30177 forms a stacked dimeric G-quadruplex structure containing bulges.

Publications

HIV-1 integrase inhibitor T30177 forms a stacked dimeric G-quadruplex structure containing bulges.

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