Targeting HIV-1 integrase with strand transfer inhibitors

Li, Yang; Xuan, Shouyi; Feng, Yue; Yan, Aixia

doi:10.1016/j.drudis.2014.12.001

Cited by 38 publications

(31 citation statements)

References 100 publications

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“…Raltegravir, Elvitegravir and Dolutegravir are IN strand-transfer inhibitors (INSTIs) approved by the FDA (US Food and Drug Administration). [8][9] These drugs exert their effect by binding to the active site. Despite their excellent safety profile and efficacy, INSTI-resistant strains have already emerged in the clinic, underscoring the importance of developing next-generation IN inhibitors.…”

mentioning

confidence: 99%

Investigation on the sucrose binding pocket of HIV-1 Integrase by molecular dynamics and synergy experiments

Tintori¹,

Esposito²,

Morreale³

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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mentioning

confidence: 99%

Investigation on the sucrose binding pocket of HIV-1 Integrase by molecular dynamics and synergy experiments

Tintori¹,

Esposito²,

Morreale³

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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“…However, only inhibitors that preferentially or specifically target the ST reaction have reached clinical use, belonging to the INSTI family. To date, from a chemical point of view, nine classes can be determined among INSTIs, based on their scaffolds (for a review, see Li et al, 2015). RAL, the first anti-integrase inhibitor approved by FDA in 2007 (Grinsztejn et al, 2007; Summa et al, 2008), was followed by EVG in 2012 and DTG in 2013, the latter belonging to the second generation of INSTI (for a review, see Serrao et al, 2009) (Hare et al, 2011).…”

Section: Targeting Hiv-1 Inmentioning

confidence: 99%

Different Pathways Leading to Integrase Inhibitors Resistance

2017

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Integrase strand-transfer inhibitors (INSTIs), such as raltegravir (RAL), elvitegravir, or dolutegravir (DTG), are efficient antiretroviral agents used in HIV treatment in order to inhibit retroviral integration. By contrast to RAL treatments leading to well-identified mutation resistance pathways at the integrase level, recent clinical studies report several cases of patients failing DTG treatment without clearly identified resistance mutation in the integrase gene raising questions for the mechanism behind the resistance. These compounds, by impairing the integration of HIV-1 viral DNA into the host DNA, lead to an accumulation of unintegrated circular viral DNA forms. This viral DNA could be at the origin of the INSTI resistance by two different ways. The first one, sustained by a recent report, involves 2-long terminal repeat circles integration and the second one involves expression of accumulated unintegrated viral DNA leading to a basal production of viral particles maintaining the viral information.

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“…HIV integrase inhibitors are based on multiple chemical scaffolds, especially the diketo- and β-keto acids (Li et al, 2014). Three drugs have been approved: raltegravir, elvitegravir, and dolutegravir (Mesplede et al, 2014).…”

Section: Rnaseh Enzymesmentioning

confidence: 99%

The hepatitis B virus ribonuclease H as a drug target

Tavis

Lomonosova

2015

Antiviral Research

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Chronic hepatitis B virus (HBV) infection is a leading cause of hepatitis, liver failure, and hepatocellular carcinoma. An outstanding vaccine is available; however the number of infections remains high. Current anti-HBV treatments with interferon α and nucleos(t)ide analogs clear the infection in only a small minority of patients, and either induce serious side-effects or are of very long duration. HBV is a small, enveloped DNA virus that replicates by reverse transcription via an RNA intermediate. The HBV ribonuclease H (RNaseH) is essential for viral replication, but it has not been exploited as a drug target. Recent low-throughput screening of compound classes with anti-Human Immunodeficiency Virus RNaseH activity led to identification of HBV RNaseH inhibitors in three different chemical families that block HBV replication. These inhibitors are promising candidates for development into new anti-HBV drugs. The RNaseH inhibitors may help improve treatment efficacy enough to clear the virus from the liver when used in combination with existing anti-HBV drugs and/or with other novel inhibitors under development. This article forms part of a symposium in Antiviral Research on “An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B.”

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Targeting HIV-1 integrase with strand transfer inhibitors

Cited by 38 publications

References 100 publications

Investigation on the sucrose binding pocket of HIV-1 Integrase by molecular dynamics and synergy experiments

Investigation on the sucrose binding pocket of HIV-1 Integrase by molecular dynamics and synergy experiments

Different Pathways Leading to Integrase Inhibitors Resistance

The hepatitis B virus ribonuclease H as a drug target

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