Strand transfer inhibitors of HIV-1 integrase: Bringing IN a new era of antiretroviral therapy

McColl, Damian J.; Chen, Xiaowu

doi:10.1016/j.antiviral.2009.11.004

Cited by 151 publications

(125 citation statements)

References 83 publications

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“…IN is responsible for the integration of viral DNA into host cell genome via a two-step process. 6,7 In the first step, IN binds to viral DNA as part of the preintegration complex (PIC) in the cytoplasm and excises a dinucleotide from each 3′-end. Following this 3′-processing event, the PIC is transported into the nucleus where the 3′-ends of viral DNA are covalently linked to the 5′-ends of the host cell DNA in a process known as strand transfer.…”

mentioning

confidence: 99%

Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1

Fader

Malenfant

Parisien

et al. 2014

ACS Med. Chem. Lett.

144

167

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An assay recapitulating the 3′ processing activity of HIV-1 integrase (IN) was used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead optimization beginning with compound 1 established the importance of the C3 and C4 substituent to antiviral potency against viruses with different aa124/ aa125 variants of IN. The importance of the C7 position on the serum shifted potency was established. Introduction of a quinoline substituent at the C4 position provided a balance of potency and metabolic stability. Combination of these findings ultimately led to the discovery of compound 26 (BI 224436), the first NCINI to advance into a phase Ia clinical trial.

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confidence: 99%

Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1

Fader

Malenfant

Parisien

et al. 2014

ACS Med. Chem. Lett.

144

167

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“…IN has been extensively studied as a therapeutic target in the field of AIDS antiretroviral therapy since it establishes irreversible infection and has no cellular equivalent, which limits toxicity. 1,2 The integration process involves a sequence of 2 reactions, which both require the presence of metallic cofactors: in the cytoplasm, a DNA-IN complex is formed that catalyzes the endonucleolytic cleavage of a dinucleotide at each 3′-end of the dsDNA (the 3′-processing step, 3′-P) After transport into the nucleus, the strand transfer step (ST), catalyzed by the intasome (a specific tetramer of IN and viral DNA ends) then joins each 3′-end of this recessed DNA to a 5′-end in the host DNA.…”

mentioning

confidence: 99%

4-Substituted 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as a Novel Class of HIV-1 Integrase Inhibitors

Billamboz

Suchaud

Bailly

et al. 2013

ACS Med. Chem. Lett.

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A series of 2-hydroxy-1,3-dioxoisoquinoline-4-carboxamides featuring an N-hydroxyimide chelating functionality was evaluated for their inhibitory properties against human immunodeficiency virus type 1 integrase (HIV-1 IN). Several derivatives displayed low nanomolar IC 50 values comparable to that of the clinically used raltegravir. A marked effect of one compound on both primary IN-catalyzed reactions, strand transfer (ST), and 3′ processing (3′-P), emphasizes a novel IN inhibition mechanism establishing it as a potential new generation IN inhibitor. Substitution of the 2-hydroxyisoquinoline-1,3-dione scaffold at position 4 by carboxamido chains was beneficial for antiviral activity since reproducible low micromolar anti-HIV activities were obtained for the first time within this scaffold.

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“…Due to its critical role in replication, human immunodeficiency virus type 1 (HIV-1) IN has long been targeted for drug development, and the first-in-class inhibitor raltegravir (RAL) was licensed in 2007 (45). Because RAL and related compounds preferentially inhibit DNA strand transfer activity, the drugs are referred to as IN strand transfer inhibitors (INSTIs) (24). Elvitegravir (EVG) is another well-studied INSTI (41).…”

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confidence: 99%

“…RSV IN harbors two amino acids, Ser150 and Gly152, that when present in HIV-1 as P145S or S147G confer significant resistance to EVG (16,24,40). To test if either or both of these residues contribute to the relative insensitivity to EVG, S150P and G152S changes were introduced into RSV IN either alone or in combination, and equivalent RT cpm of VSV-G-pseudotyped virions were used to infect cells.…”

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confidence: 99%

“…2). To facilitate interpretation, residues that when altered can contribute to HIV-1 resistance were color coded green, and amino acid differences known to confer resistance, magenta (9,16,24,40); gray represents changes whose contributions to drug resistance are unknown. BIV IN carries His at the position corresponding to Asn155 in HIV-1 IN, perhaps contributing to its 23-fold-reduced sensitivity to RAL (Fig.…”

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confidence: 99%

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Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

Koh

Matreyek

Engelman

2011

J Virol

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Integrase inhibitors are emerging anti-human immunodeficiency virus (HIV) drugs, and multiple retroviruses and transposable elements were evaluated here for susceptibilities to raltegravir (RAL) and elvitegravir (EVG). All viruses, including primate and nonprimate lentiviruses, a Betaretrovirus, a Gammaretrovirus, and the Alpharetrovirus Rous sarcoma virus (RSV), were susceptible to inhibition by RAL. EVG potently inhibited all lentiviruses and intermediately inhibited Betaretrovirus and Gammaretrovirus infections yet was basically ineffective against RSV. Substitutions based on HIV type 1 (HIV-1) resistance changes revealed that integrase residue Ser150 contributed significantly to the resistance of RSV. The drugs intermediately inhibited intracisternal A-particle retrotransposition but were inactive against Sleeping Beauty transposition and long interspersed nucleotide element 1 (LINE-1) retrotransposition.Reverse transcription of retroviral RNA yields linear viral DNA (vDNA) containing a copy of the long terminal repeat (LTR) at each end. Integrase (IN) is an essential retroviral enzyme that catalyzes two reactions to insert the vDNA into cellular chromosomal DNA. IN prepares the LTR ends by hydrolyzing phosphodiester bonds adjacent to invariant CA dinucleotides, yielding reactive 3Ј deoxyadenylate (dA OH ) termini. In the nucleus, IN catalyzes DNA strand transfer by using the 3Ј OHs to cut the chromosome in a staggered fashion, concomitantly joining the vDNA ends to 5Ј phosphates. Hostmediated repair of the resulting DNA recombination intermediate completes the integration process. See reference 8 for an overview of retroviral reverse transcription and integration.IN belongs to the polynucleotidyl transferase superfamily of nucleic acid-metabolizing enzymes (7). Conserved amino acid residues (typically Asp and Glu [32]) arranged commonly on an RNase H structural fold comprise active sites that coordinate divalent metal ions for in-line nucleophilic attack of phosphodiester bonds. Due to its critical role in replication, human immunodeficiency virus type 1 (HIV-1) IN has long been targeted for drug development, and the first-in-class inhibitor raltegravir (RAL) was licensed in 2007 (45). Because RAL and related compounds preferentially inhibit DNA strand transfer activity, the drugs are referred to as IN strand transfer inhibitors (INSTIs) (24). Elvitegravir (EVG) is another well-studied INSTI (41). Recently determined X-ray crystal structures revealed that the drugs work by ejecting the 3Ј dA and its associated OH nucleophile from the IN active site (10,

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Strand transfer inhibitors of HIV-1 integrase: Bringing IN a new era of antiretroviral therapy

Cited by 151 publications

References 83 publications

Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1

Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1

4-Substituted 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as a Novel Class of HIV-1 Integrase Inhibitors

Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

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