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

Fader, L. D.; Malenfant, Éric; Parisien, Mathieu; Carson, Rebekah; Bilodeau, François; Landry, Serge; Pesant, Marc; Brochu, Christian; Morin, Sébastien; Chabot, Catherine; Halmos, Ted; Bousquet, Yves; Bailey, Murray; Kawai, Stephen H.; Coulombe, René; LaPlante, Steven R.; Jakalian, Araz; Bhardwaj, Punit Kumar; Wernic, Dominik; Schroeder, Patricia; Amad, Ma’an; Edwards, Paul; Garneau, Michel; Duan, Jianmin; Cordingley, Michael G.; Bethell, Richard C.; Mason, Stephen W.; Bös, Michael; Bonneau, Pierre; Poupart, Marc‐André; Faucher, Anne‐Marie; Simoneau, Bruno; Fenwick, Craig; Yoakim, Christiane; Tsantrizos, Youla S.

doi:10.1021/ml500002n

Cited by 148 publications

(177 citation statements)

References 23 publications

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“…The initial hit from the NCINI series was identified using a fluorescence-based assay with an LTR DNA probe to measure the 3=-processing enzymatic activity of HIV-1 integrase. Medicinal chemistry optimization combined with rational design based on our understanding of the binding mode of our inhibitors led to the identification of our first development candidate, BI 224436 (18). A mean IC 50 of 15 Ϯ 4 nM was obtained for BI 224436 with the LTR 3=-processing assay (see Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Using an integrase LTR DNA 3=-processing assay in a highthroughput format, we identified a 3-quinolineacetic acid series that specifically inhibited the 3=-processing step catalyzed by integrase (18,19). After preliminary optimization in hit-to-lead chemistry, biochemical assays showed that in addition to inhibiting the 3=-processing step, this series also inhibited the LTR DNA interaction with integrase and the interaction between integrase and LEDGF without inhibiting the strand transfer activity of integrase (S. Mason and C. Fenwick, unpublished data).…”

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confidence: 99%

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Preclinical Profile of BI 224436, a Novel HIV-1 Non-Catalytic-Site Integrase Inhibitor

Fenwick

Amad

Bailey

et al. 2014

Antimicrob Agents Chemother

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BI 224436 is an HIV-1 integrase inhibitor with effective antiviral activity that acts through a mechanism that is distinct from that of integrase strand transfer inhibitors (INSTIs). This 3-quinolineacetic acid derivative series was identified using an enzymatic integrase long terminal repeat (LTR) DNA 3=-processing assay. A combination of medicinal chemistry, parallel synthesis, and structure-guided drug design led to the identification of BI 224436 as a candidate for preclinical profiling. It has antiviral 50% effective concentrations (

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Preclinical Profile of BI 224436, a Novel HIV-1 Non-Catalytic-Site Integrase Inhibitor

Fenwick

Amad

Bailey

et al. 2014

Antimicrob Agents Chemother

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120

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“…[33][34][35][36]. These compounds bind at the IN CCD dimer interface occupying the principal LEDGF/p75 binding pocket (12,(37)(38)(39)(40)(41)(42).…”

Section: Hiv-1 Integrase (In)mentioning

confidence: 99%

A Critical Role of the C-terminal Segment for Allosteric Inhibitor-induced Aberrant Multimerization of HIV-1 Integrase

Shkriabai

Dharmarajan

Slaughter

et al. 2014

Journal of Biological Chemistry

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Background: Allosteric integrase (IN) inhibitors (ALLINIs) promote aberrant protein multimerization. Results: ALLINI-2 induces protein-protein interactions, including C-terminal residues Lys-264 and Lys-266, which lead to aberrant, higher-order IN multimerization. Conclusion: The protein-protein contacts beyond the inhibitor binding site contribute to aberrant IN multimerization. Significance: Our findings provide structural clues and underscore the significance for exploiting IN multimerization as a new therapeutic target.

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“…In these particles, the viral ribonucleoprotein complexes (vRNPs), mainly composed of the viral genomic RNA and NC, are eccentrically localized between the empty CA lattice and the viral membrane (7,9,17). A remarkably similar morphological defect is observed in particles generated in the presence of allosteric integrase inhibitors (ALLINIs) (also known as LEDGINs, NCINIs, or INLAIs) (18)(19)(20)(21)(22)(23). Proposed mechanisms that underlie this morphogenesis defect include ALLINI-induced aberrant IN multimerization (9,17,(24)(25)(26)(27) and inhibition of IN binding to the viral RNA genome (4).…”

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confidence: 96%

Allosteric HIV-1 Integrase Inhibitors Lead to Premature Degradation of the Viral RNA Genome and Integrase in Target Cells

Madison

Lawson

Elliott

et al. 2017

J Virol

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Recent evidence indicates that inhibition of HIV-1 integrase (IN) binding to the viral RNA genome by allosteric integrase inhibitors (ALLINIs) or through mutations within IN yields aberrant particles in which the viral ribonucleoprotein complexes (vRNPs) are eccentrically localized outside the capsid lattice. These particles are noninfectious and are blocked at an early reverse transcription stage in target cells. However, the basis of this reverse transcription defect is unknown. Here, we show that the viral RNA genome and IN from ALLINI-treated virions are prematurely degraded in target cells, whereas reverse transcriptase remains active and stably associated with the capsid lattice. The aberrantly shaped cores in ALLINI-treated particles can efficiently saturate and be degraded by a restricting TRIM5 protein, indicating that they are still composed of capsid proteins arranged in a hexagonal lattice. Notably, the fates of viral core components follow a similar pattern in cells infected with eccentric particles generated by mutations within IN that inhibit its binding to the viral RNA genome. We propose that IN-RNA interactions allow packaging of both the viral RNA genome and IN within the protective capsid lattice to ensure subsequent reverse transcription and productive infection in target cells. Conversely, disruption of these interactions by ALLINIs or mutations in IN leads to premature degradation of both the viral RNA genome and IN, as well as the spatial separation of reverse transcriptase from the viral genome during early steps of infection.IMPORTANCE Recent evidence indicates that HIV-1 integrase (IN) plays a key role during particle maturation by binding to the viral RNA genome. Inhibition of IN-RNA interactions yields aberrant particles with the viral ribonucleoprotein complexes (vRNPs) eccentrically localized outside the conical capsid lattice. Although these particles contain all of the components necessary for reverse transcription, they are blocked at an early reverse transcription stage in target cells. To explain the basis of this defect, we tracked the fates of multiple viral components in infected cells. Here, we show that the viral RNA genome and IN in eccentric particles are prematurely degraded, whereas reverse transcriptase remains active and stably associated within the capsid lattice. We propose that IN-RNA interactions ensure the packaging of both vRNPs and IN within the protective capsid cores to facilitate subsequent reverse transcription and productive infection in target cells.KEYWORDS ALLINIs, capsid, HIV-1, integrase, maturation, protein-RNA interaction, RNA packaging, TRIM5, reverse transcriptase

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

Cited by 148 publications

References 23 publications

Preclinical Profile of BI 224436, a Novel HIV-1 Non-Catalytic-Site Integrase Inhibitor

Preclinical Profile of BI 224436, a Novel HIV-1 Non-Catalytic-Site Integrase Inhibitor

A Critical Role of the C-terminal Segment for Allosteric Inhibitor-induced Aberrant Multimerization of HIV-1 Integrase

Allosteric HIV-1 Integrase Inhibitors Lead to Premature Degradation of the Viral RNA Genome and Integrase in Target Cells

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