Broad Antiretroviral Activity and Resistance Profile of the Novel Human Immunodeficiency Virus Integrase Inhibitor Elvitegravir (JTK-303/GS-9137)

Shimura, Kazuya; Kodama, Eiichi; Sakagami, Yasuko; Matsuzaki, Yuji; Watanabe, Wataru; Yamataka, Kazunobu; Watanabe, Yasunori; Ohata, Yoshitsugu; Doi, Satoki; Sato, Motohide; Kano, Mitsuki; Ikeda, Satoru; Matsuoka, Masao

doi:10.1128/jvi.01534-07

Cited by 308 publications

(270 citation statements)

References 51 publications

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“…1C). In addition, it is of note that the dose-dependent and specific inhibition of in vitro PIC activity has also been shown in the treatment with a well documented HIV-1 IN strand transfer inhibitor, elvitegravir (data not shown), with an IC 50 of 2.6 nM, which was a similar, subnanomolar range of EC 50 obtained by cell-based HIV infection assay (33). Taken together, these data show that the microtiter plate-based assay is an adequate system to quantitatively detect in vitro HIV-1 PIC integration events and their modulation by cellular proteins.…”

Section: Application Of the Microtiter Plate-based Hiv-1 Pic Assay Tosupporting

confidence: 49%

Identification of RFPL3 Protein as a Novel E3 Ubiquitin Ligase Modulating the Integration Activity of Human Immunodeficiency Virus, Type 1 Preintegration Complex Using a Microtiter Plate-based Assay

Tan

Suzuki

Takahashi

et al. 2014

Journal of Biological Chemistry

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Background:The retroviral preintegration complex (PIC) exhibits full fidelity of integration in vitro. Results: Application of a protein library to the microplate-based integration assay identified RFPL3 as an enhancer of HIV-1 PIC activity. Conclusion: This screening platform permits efficient identification of cellular factors modulating PIC. Significance: This approach provides an advantage in advancing our understanding of virus-host interactions in retrovirus integration.

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Section: Application Of the Microtiter Plate-based Hiv-1 Pic Assay Tosupporting

confidence: 49%

Identification of RFPL3 Protein as a Novel E3 Ubiquitin Ligase Modulating the Integration Activity of Human Immunodeficiency Virus, Type 1 Preintegration Complex Using a Microtiter Plate-based Assay

Tan

Suzuki

Takahashi

et al. 2014

Journal of Biological Chemistry

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“…In this study we report detailed in vitro biochemical analyses of purified integrase enzymes containing substitutions resulting in decreased sensitivity to STIs. These include the reported previously substitutions T66I, V75I, E92Q, Q148R, and N155H and M154I (17)(18)(19)(20)(21)(22). We have also examined combinations of these changes (T66I/E92Q, T66I/N155H, and V75I/M154I).…”

Section: Hiv-1mentioning

confidence: 99%

Biochemical Analysis of HIV-1 Integrase Variants Resistant to Strand Transfer Inhibitors

Dicker

Terry

Lin

et al. 2008

Journal of Biological Chemistry

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In this study, eight different HIV-1 integrase proteins containing mutations observed in strand transfer inhibitor-resistant viruses were expressed, purified, and used for detailed enzymatic analyses. All the variants examined were impaired for strand transfer activity compared with the wild type enzyme, with relative catalytic efficiencies (k p /K m ) ranging from 0.6 to 50% of wild type. The origin of the reduced strand transfer efficiencies of the variant enzymes was predominantly because of poorer catalytic turnover (k p ) values. However, smaller secondorder effects were caused by up to 4-fold increases in K m values for target DNA utilization in some of the variants. All the variants were less efficient than the wild type enzyme in assembling on the viral long terminal repeat, as each variant required more protein than wild type to attain maximal activity. In addition, the variant integrases displayed up to 8-fold reductions in their catalytic efficiencies for 3-processing. The Q148R variant was the most defective enzyme. The molecular basis for resistance of these enzymes was shown to be due to lower affinity binding of the strand transfer inhibitor to the integrase complex, a consequence of faster dissociation rates. In the case of the Q148R variant, the origin of reduced compound affinity lies in alterations to the active site that reduce the binding of a catalytically essential magnesium ion. Finally, except for T66I, variant viruses harboring the resistance-inducing substitutions were defective for viral integration.

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“…Significant progress was achieved with the development of an assay that identified compounds that specifically inhibited ST [56], aiding the discovery of a series of related inhibitors including the lead compounds MK-0518 and GS-9137. These lead compounds have been shown to inhibit potently HIV-1 integration at nanomolar concentrations In vitro [60][61][62][63][64][65] and block HIV-1 replication In vivo [58,[66][67][68][69]. The functional commonality shared by this family of compounds is a diketo acid or structurally related derivative, with a diketo or diketo-like group linking a coplanar acid group and an aromatic group.…”

Section: Integrase Inhibitorsmentioning

confidence: 99%

“…In vitro selection studies mapped the majority of resistance-conferring mutations to residues clustered around the IN catalytic active site (the DDE motif) [60,63,65,73,74]. The close proximity of resistance-conferring mutations to the enzyme's active site establishes IN as the target of viral inhibition.…”

Section: Integrase Inhibitorsmentioning

confidence: 99%

Recent progress in antiretrovirals – lessons from resistance

Adamson

Freed

2008

Drug Discovery Today

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Recent failures in efforts to develop an effective vaccine against HIV-1 infection have emphasized the importance of antiretroviral therapy in treating HIV-1-infected patients. Thus far, inhibitors of two viral enzymes, reverse transcriptase and protease, have had a profoundly positive impact on the survival of HIV-1-infected patients. However, new inhibitors that act at diverse steps in the viral replication cycle are urgently needed because of the development of resistance to currently available antiretrovirals. This review summarizes recent progress in antiretroviral drug discovery and development by specifically focusing on novel inhibitors of three phases of replication: viral entry, integration of the viral DNA into the host cell genome and virus particle maturation.

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Broad Antiretroviral Activity and Resistance Profile of the Novel Human Immunodeficiency Virus Integrase Inhibitor Elvitegravir (JTK-303/GS-9137)

Abstract: Integrase (IN), an essential enzyme of human immunodeficiency virus (HIV),

Cited by 308 publications

References 51 publications

Identification of RFPL3 Protein as a Novel E3 Ubiquitin Ligase Modulating the Integration Activity of Human Immunodeficiency Virus, Type 1 Preintegration Complex Using a Microtiter Plate-based Assay

Identification of RFPL3 Protein as a Novel E3 Ubiquitin Ligase Modulating the Integration Activity of Human Immunodeficiency Virus, Type 1 Preintegration Complex Using a Microtiter Plate-based Assay

Biochemical Analysis of HIV-1 Integrase Variants Resistant to Strand Transfer Inhibitors

Recent progress in antiretrovirals – lessons from resistance

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