HIV Integrase Inhibitors

Métifiot, Mathieu; Marchand, Christophe; Pommier, ﻿Yves

doi:10.1016/b978-0-12-405880-4.00003-2

Cited by 60 publications

(37 citation statements)

References 112 publications

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“…Here, we performed biochemical experiments and molecular modeling with the WT and the double-mutant (G140S-Q148H [SH]) that causes significant resistance to RAL and EVG and to a lesser extent to DTG (2,11,12,22,26). Viral DNA substrates with modifications at positions +1 and −1 were tested to probe the 3′-P activity of WT and SH IN enzymes in the absence and presence of RAL and DTG.…”

Section: Discussionmentioning

confidence: 99%

Selectivity for strand-transfer over 3′-processing and susceptibility to clinical resistance of HIV-1 integrase inhibitors are driven by key enzyme–DNA interactions in the active site

et al. 2016

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Integrase strand transfer inhibitors (INSTIs) are highly effective against HIV infections. Co-crystal structures of the prototype foamy virus intasome have shown that all three FDA-approved drugs, raltegravir (RAL), elvitegravir and dolutegravir (DTG), act as interfacial inhibitors during the strand transfer (ST) integration step. However, these structures give only a partial sense for the limited inhibition of the 3′-processing reaction by INSTIs and how INSTIs can be modified to overcome drug resistance, notably against the G140S-Q148H double mutation. Based on biochemical experiments with modified oligonucleotides, we demonstrate that both the viral DNA +1 and −1 bases, which flank the 3′-processing site, play a critical role for 3′-processing efficiency and inhibition by RAL and DTG. In addition, the G140S-Q148H (SH) mutant integrase, which has a reduced 3′-processing activity, becomes more active and more resistant to inhibition of 3′-processing by RAL and DTG in the absence of the −1 and +1 bases. Molecular modeling of HIV-1 integrase, together with biochemical data, indicate that the conserved residue Q146 in the flexible loop of HIV-1 integrase is critical for productive viral DNA binding through specific contacts with the virus DNA ends in the 3′-processing and ST reactions. The potency of integrase inhibitors against 3′-processing and their ability to overcome resistance is discussed.

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Section: Discussionmentioning

confidence: 99%

Selectivity for strand-transfer over 3′-processing and susceptibility to clinical resistance of HIV-1 integrase inhibitors are driven by key enzyme–DNA interactions in the active site

et al. 2016

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“…They are currently three FDA-approved INSTIs: raltegravir, elvitegravir and the best in class dolutegravir. 29 Integrase is required for HIV replication because it is responsible for inserting the viral DNA in the host chromosome. 30 The INSTIs prevent integrase from performing its catalytic reaction by blocking the enzyme after it completes its initial cleavage step, which is referred to as 3'-processing, that activates the proviral DNA before integrase can catalyze the second transesterification step, referred to as strand transfer.…”

Section: Top2 Inhibitorsmentioning

confidence: 99%

Interfacial inhibitors

Pommier

Kiselev

Marchand

2015

Bioorganic & Medicinal Chemistry Letters

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Targeting macromolecular interface is a general mechanism by which natural products inactivate macromolecular complexes by stabilizing normally transient intermediates. Demonstrating interfacial inhibition mechanism ultimately relies on the resolution of drug-macromolecule structures. This review focuses on medicinal drugs that trap protein-DNA complexes by binding at protein-DNA interfaces. It provides proof-of-concept and detailed structural and mechanistic examples for topoisomerase inhibitors and HIV integrase inhibitors. Additional examples of recent interfacial inhibitors for protein-DNA interfaces are provided, as well as prospects for targeting previously 'undruggable' targets including transcription, replication and chromatin remodeling complexes. References and discussion are included for interfacial inhibitors of protein-protein interfaces.

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“…Several chemical families were explored before the pyrimidinone group was identified. Extensive development eventually yielded raltegravir, which received FDA approval in 2007 (132). …”

Section: Inhibitors Of Hiv Integrationmentioning

confidence: 99%

Host Factors in Retroviral Integration and the Selection of Integration Target Sites

Craigie

Bushman

2014

Microbiol Spectr

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In order to replicate, a retrovirus must integrate a DNA copy of the viral RNA genome into a chromosome of the host cell. The study of retroviral integration has advanced considerably in the last few years. Here we focus on host factor interactions and the linked area of integration targeting. Genome-wide screens for cellular factors affecting HIV replication have identified a series of host cell proteins that may mediate subcellular trafficking of integration complexes, nuclear import, and integration target site selection. The cell transcriptional co-activator protein LEDGF/p75 has been identified as a tethering factor important for HIV integration, and recently, BET proteins (Brd2, 4, and 4) have been identified as tethering factors for the gammaretroviruses. A new class of HIV inhibitors has been developed targeting the HIV-1 IN-LEDGF binding site, though surprisingly these inhibitors appear to block assembly late during replication and do not act at the integration step. Going forward, genome-wide studies of HIV-host interactions offer many new starting points to investigate HIV replication and identify potential new inhibitor targets.

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HIV Integrase Inhibitors

Cited by 60 publications

References 112 publications

Selectivity for strand-transfer over 3′-processing and susceptibility to clinical resistance of HIV-1 integrase inhibitors are driven by key enzyme–DNA interactions in the active site

Selectivity for strand-transfer over 3′-processing and susceptibility to clinical resistance of HIV-1 integrase inhibitors are driven by key enzyme–DNA interactions in the active site

Interfacial inhibitors

Host Factors in Retroviral Integration and the Selection of Integration Target Sites

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