Identification of a Novel Sulfonamide Non-Nucleoside Reverse Transcriptase Inhibitor by a Phenotypic HIV-1 Full Replication Assay

Kim, Tae Hee; Ko, Yoonae; Christophe, Thierry; Cechetto, Jonathan; Kim, Jun Won; Kim, Kyoung Ae; Boese, Annette; Garcia, Jean‐Michel; Fenistein, Denis; Ju, Moon Kyeong; Kim, Junghwan; Han, Sung‐Jun; Kwon, Ho Jeong; Brondani, Vincent; Sommer, Peter

doi:10.1371/journal.pone.0068767

Cited by 5 publications

(6 citation statements)

References 22 publications

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“…Integrase inhibitors act for up to 18 h, and protease inhibitors are effective for 15 h, which is nearly the complete replication cycle. Such results were similarly obtained in several other studies [11,[34][35][36][37].…”

Section: These Results Show That Tae-luc Is a Useful Tool To Delimitsupporting

confidence: 88%

“…Our TAE-luc has the advantage of being a sensitive, highthroughput, target-based screening bioluminescence assay that is faster than counting blue cells [27] or syncytia formations [38,39], which are also less sensitive assays. As the HeLa cells are attached to the bottom of the well, it is easier to handle them, in contrast to the GFP cells [40,41], which are unattached or loose in the media. By adding the luciferase reagent, virus infection can be immediately quantified.…”

Section: These Results Show That Tae-luc Is a Useful Tool To Delimitmentioning

confidence: 99%

“…Screening and testing the target of a novel ARV are important steps in antiviral innovation. Recently, screening assays have become essential for early-phase ARV discovery because of the advancement in drug synthesis technologies and because of a considerable increase in new pharmacologic targets [11,14,15].…”

Section: Screening Assaysmentioning

confidence: 99%

“…There have been several studies on the mechanism of action of newly discovered HIV inhibitors, including virus-based assays, structure-based drug design, receptor pharmacology, biochemical screening, time-of-addition experiments and bioluminescence assays [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Luciferase Time-based, High-throughput Screening Assay for the Discovery of HIV-1 Inhibitors

Lara¹

2014

JHVRV

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With the enhancement of high-throughput screening (HTS) for target-based antiretroviral discovery, fluorescence has been considered the best bioassay. Bioluminescence by genetic reporters has maintained a major place among cell-based virological assay formats. Luminescent bioassays have a wide variety of applications due to their high sensitivity and linearity, even for a range of complex biological samples. In this target-based method, we used an HTS bioluminescence assay and highlighted the detection capabilities of this time-of-addition experiment. Hence, the development of a cell-based assay that uses a phenotypic drug discovery approach based on bioluminescence by stable reporter cells is described. Utilizing this screening method, a bioluminescent, target-based, time-of-addition experiment was performed by adding antiretrovirals with known mechanisms of action to analyze their drug targets by measuring the length of time until the antiretrovirals lost their efficacy in an HIV-1 replication assay. Depending on the viral replication target, the antiretrovirals lost activity at different times: fusion inhibitors acted for 0-2 h; retrotranscriptase inhibitors acted efficiently for the first 4 h; integrase inhibitors acted for 18 h; and protease inhibitors were inactivated after 15 h. The target-based, bioluminescence assay identifies the mode of action of antiretroviral drugs and provides valuable information about drug targets that inhibit HIV replication. This assay delimits the time (hours) for which the addition of an antiviral can be delayed before losing its antiviral activity relative to the replication cycle of HIV. The target of an antiviral compound can be identified both by comparing the relative time until it loses efficacy to that of the reference drugs and by the time elapsed when the antiretroviral loses activity compared to a known control. Our target-based bioluminescence assay is fast, reliable, sensitive and useful for highthroughput drug screening.

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Section: These Results Show That Tae-luc Is a Useful Tool To Delimitsupporting

confidence: 88%

Section: These Results Show That Tae-luc Is a Useful Tool To Delimitmentioning

confidence: 99%

Section: Screening Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Luciferase Time-based, High-throughput Screening Assay for the Discovery of HIV-1 Inhibitors

Lara¹

2014

JHVRV

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“…Other recently reported NNRTIs include a 2,4,5-trisubstituted thiazole derivatives [39] and a novel sulfonamide compound IPK1 [40]. The thiazole derivatives inhibited RT activity at low micromolar concentrations and were effective against NNRTI-resistant strains of HIV-1.…”

Section: Novel Nnrtis: Promising Compoundsmentioning

confidence: 99%

Investigational reverse transcriptase inhibitors for the treatment of HIV

Cory

Midde

Rao

et al. 2015

Expert Opinion on Investigational Drugs

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Introduction While considerable advances have been made in the development of antiretroviral agents, there is still work to be done. Reverse transcriptase inhibitors are important drugs for the treatment of HIV, and considerable research is currently ongoing to develop new agents and to modify currently existing agents. Areas covered Herein, the authors discuss both investigational nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), including agents that are in various stages of development. They also discuss novel formulations that are being investigated for currently available drugs, and discuss the advantages that these new formulations may provide. Expert opinion New formulations and co-formulations of currently existing antiretrovirals will represent an important area of development, as a means to improve adherence for HIV-positive individuals. New formulations will continue to be developed, with a focus on allowing for less-frequent administration, as well increasing drug concentrations at local sites such as vaginal tissue, rectal tissue and sites in the immune system.

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A new class of HIV-1 inhibitors and the target identification via proteomic profiling

Zhou

Xiao

et al. 2018

Sci. China Chem.

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Identification of a Novel Sulfonamide Non-Nucleoside Reverse Transcriptase Inhibitor by a Phenotypic HIV-1 Full Replication Assay

Cited by 5 publications

References 22 publications

Luciferase Time-based, High-throughput Screening Assay for the Discovery of HIV-1 Inhibitors

Luciferase Time-based, High-throughput Screening Assay for the Discovery of HIV-1 Inhibitors

Investigational reverse transcriptase inhibitors for the treatment of HIV

A new class of HIV-1 inhibitors and the target identification via proteomic profiling

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