Analysis of binding parameters of HIV-1 integrase inhibitors: Correlates of drug inhibition and resistance

Loizidou, Eriketi Z.; Zeinalipour-Yazdi, Constantinos D.; Christofides, Tasos C.; Kostrikis, Leondios G.

doi:10.1016/j.bmc.2009.04.058

Cited by 15 publications

(12 citation statements)

References 55 publications

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“…Primary resistance to raltegravir has been associated with three major mutations, N155H, Q148H/K/R, and Y143H; mutation of any of these HIV-1 IN amino acids initiates pathways leading to raltegravir resistance [22,38,39]. These residues are located around the active site of IN and within interacting distance to raltegravir, as shown by molecular modelling simulations conducted by independent groups [27,40]. Drug resistance mutations N155H and Q148R were shown to hamper INSTI binding to HIV-1 IN, by either decreasing the affinity of IN/proviral DNA complexes for INSTIs (N155H) or affecting assembly of proviral DNA (Q148R) [41].…”

Section: Discussionmentioning

confidence: 99%

“…Drug resistance mutations N155H and Q148R were shown to hamper INSTI binding to HIV-1 IN, by either decreasing the affinity of IN/proviral DNA complexes for INSTIs (N155H) or affecting assembly of proviral DNA (Q148R) [41]. Secondary mutations reported for raltegravir are L74M, E92Q, T97A, E138K, G140S/A, V151I, G163R, I203M, S230R, and D232N [22,38,40]. …”

Section: Discussionmentioning

confidence: 99%

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Response of a simian immunodeficiency virus (SIVmac251) to raltegravir: a basis for a new treatment for simian AIDS and an animal model for studying lentiviral persistence during antiretroviral therapy

et al. 2010

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BackgroundIn this study we successfully created a new approach to ART in SIVmac251 infected nonhuman primates. This drug regimen is entirely based on drugs affecting the pre-integration stages of replication and consists of only two nucleotidic/nucleosidic reverse transcriptase inhibitors (Nt/NRTIs) and raltegravir, a promising new drug belonging to the integrase strand transfer inhibitor (INSTI) class.ResultsIn acutely infected human lymphoid CD4+ T-cell lines MT-4 and CEMx174, SIVmac251 replication was efficiently inhibited by raltegravir, which showed an EC90 in the low nanomolar range. This result was confirmed in primary macaque PBMCs and enriched CD4+ T cell fractions. In vivo monotherapy with raltegravir for only ten days resulted in reproducible decreases in viral load in two different groups of animals. When emtricitabine (FTC) and tenofovir (PMPA) were added to treatment, undetectable viral load was reached in two weeks, and a parallel increase in CD4 counts was observed. In contrast, the levels of proviral DNA did not change significantly during the treatment period, thus showing persistence of this lentiviral reservoir during therapy.ConclusionsIn line with the high conservation of the three main amino acids Y143, Q148 and N155 (responsible for raltegravir binding) and molecular docking simulations showing similar binding modes of raltegravir at the SIVmac251 and HIV-1 IN active sites, raltegravir is capable of inhibiting SIVmac251 replication both in tissue culture and in vivo. This finding may help to develop effective ART regimens for the simian AIDS model entirely based on drugs adopted for treatment in humans. This ART-treated AIDS nonhuman primate model could be employed to find possible strategies for virus eradication from the body.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Response of a simian immunodeficiency virus (SIVmac251) to raltegravir: a basis for a new treatment for simian AIDS and an animal model for studying lentiviral persistence during antiretroviral therapy

et al. 2010

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“…The protein was dialyzed against buffer B (20 mM HEPES, pH 7.5, 1 mM EDTA, 1 M NaCl, 20% glycerol) containing 2 mM ␤-mercaptoethanol, and then against buffer B containing 1 mM dithiothreitol. Aliquots of the protein were stored at −70 • C (Loizidou et al 2009).…”

Section: Assay Of Ability To Inhibit Hiv-1 Integrase Expression and Pmentioning

confidence: 99%

“…The absorbance due to the alkaline phosphatase reaction was measured at 415 nm. The ribosome inactivating protein trichosanthin was used as a positive control (Loizidou et al 2009).…”

Section: Hiv-1 Integrase Assaymentioning

confidence: 99%

An antifungal defensin from Phaseolus vulgaris cv. ‘Cloud Bean’

Jian

Zhang

et al. 2011

Phytomedicine

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An antifungal peptide with a defensin-like sequence and exhibiting a molecular mass of 7.3kDa was purified from dried seeds of Phaseolus vulgaris 'Cloud Bean'. The isolation procedure entailed anion exchange chromatography on DEAE-cellulose, affinity chromatography an Affi-gel blue gel, cation exchange chromatography on SP-Sepharose, and gel filtration by fast protein liquid chromatography on Superdex 75. Although the antifungal peptide was unadsorbed on DEAE-cellulose, it was adsorbed on both Affi-gel blue gel and SP-Sepharose. The antifungal peptide exerted antifungal activity against Mycosphaerella arachidicola with an IC(50) value of 1.8 μM. It was also active against Fusarium oxysporum with an IC(50) value of 2.2 μM. It had no inhibitory effect on HIV-1 reverse transcriptase when tested up to 100 μM. Proliferation of L1210 mouse leukemia cells and MBL2 lymphoma cells was inhibited by the antifungal peptide with an IC(50) of 10 μM and 40 μM, respectively.

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“…Although obtained in the absence of viral DNA it is assumed that the interactions between 5-CITEP and IN observed in this structure at least partly mimic the contacts between IN and DNA (Figure 3B), justifying the use of the integrase CCD•5CITEP complex as a surrogate platform for docking simulations [81]. This model was used to study the mode of binding of raltegravir [64]. Two conformations of raltegravir, differing in the nature of the interacting residues and the method of Mg 2 chelation, were obtained (Figure 4A and 4B).…”

Section: Structure-based Analysis Of Integrase/raltegravir Interacmentioning

confidence: 99%

Raltegravir: molecular basis of its mechanism of action

Mouscadet

Tchertanov

2009

Eur J Med Res

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Integration of the HIV-1 viral DNA generated by reverse transcription of the RNA genome into the host cell chromosomes is a key step of viral replication, catalyzed by the viral integrase. In October 2007, the first integrase inhibitor, raltegravir, was approved for clinical use under the name of Isentress™. The results of the various clinical trials that have evaluated raltegravir have been very encouraging with regard to the immunological and virological efficacy and tolerance. However, as observed for other anti-retrovirals, specific resistance mutations have been identified in patients failing to respond to treatment with raltegravir. Although knowledge of the integrase structural biology remains fragmentary, the structures and modeling data available might provide relevant clues on the origin of the emergence of these resistance mutations. In this review, we describe the mechanism of action of this drug and the main data relating to its use in vivo, together with recent structural data important to our understanding of the origin of viral resistance.

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Analysis of binding parameters of HIV-1 integrase inhibitors: Correlates of drug inhibition and resistance

Cited by 15 publications

References 55 publications

Response of a simian immunodeficiency virus (SIVmac251) to raltegravir: a basis for a new treatment for simian AIDS and an animal model for studying lentiviral persistence during antiretroviral therapy

Response of a simian immunodeficiency virus (SIVmac251) to raltegravir: a basis for a new treatment for simian AIDS and an animal model for studying lentiviral persistence during antiretroviral therapy

An antifungal defensin from Phaseolus vulgaris cv. ‘Cloud Bean’

Raltegravir: molecular basis of its mechanism of action

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