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Peter Cherepanov - One of the best experts on this subject based on the ideXlab platform.
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structural basis of second generation HIV Integrase inhibitor action and viral resistance
Science, 2020Co-Authors: Nicola J Cook, Denes Berta, Magd Badaoui, Allison Ballandrascolas, Andrea Nans, A Kotecha, Edina Rosta, Alan Engelman, Peter CherepanovAbstract:Although second-generation HIV Integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in Integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics.
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structure guided optimization of HIV Integrase strand transfer inhibitors
Journal of Medicinal Chemistry, 2017Co-Authors: Xue Zhi Zhao, Christophe Marchand, Yves Pommier, Peter Cherepanov, Steven J Smith, D P Maskell, Mathieu Metifiot, Valerie E Pye, Katherine FesenAbstract:Integrase mutations can reduce the effectiveness of the first-generation FDA-approved Integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogues of this scaffold. While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with t...
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HIV 1 Integrase strand transfer inhibitors with reduced susceptibility to drug resistant mutant Integrases
ACS Chemical Biology, 2016Co-Authors: Xue Zhi Zhao, Christophe Marchand, Yves Pommier, Peter Cherepanov, Steven J Smith, D P Maskell, Mathieu Metifiot, Valerie E Pye, Katherine Fesen, Stephen H HughesAbstract:HIV Integrase (IN) strand transfer inhibitors (INSTIs) are among the newest anti-AIDS drugs; however, mutant forms of IN can confer resistance. We developed noncytotoxic naphthyridine-containing INSTIs that retain low nanomolar IC50 values against HIV-1 variants harboring all of the major INSTI-resistant mutations. We found by analyzing crystal structures of inhibitors bound to the IN from the prototype foamy virus (PFV) that the most successful inhibitors show striking mimicry of the bound viral DNA prior to 3′-processing and the bound host DNA prior to strand transfer. Using this concept of “bi-substrate mimicry,” we developed a new broadly effective inhibitor that not only mimics aspects of both the bound target and viral DNA but also more completely fills the space they would normally occupy. Maximizing shape complementarity and recapitulating structural components encompassing both of the IN DNA substrates could serve as a guiding principle for the development of new INSTIs.
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retroviral intasome assembly and inhibition of dna strand transfer
Nature, 2010Co-Authors: Stephen Hare, Alan Engelman, S S Gupta, Eugene Valkov, Peter CherepanovAbstract:Integrase is an essential retroviral enzyme that binds both termini of linear viral DNA and inserts them into a host cell chromosome. The structure of full-length retroviral Integrase, either separately or in complex with DNA, has been lacking. Furthermore, although clinically useful inhibitors of HIV Integrase have been developed, their mechanism of action remains speculative. Here we present a crystal structure of full-length Integrase from the prototype foamy virus in complex with its cognate DNA. The structure shows the organization of the retroviral intasome comprising an Integrase tetramer tightly associated with a pair of viral DNA ends. All three canonical Integrase structural domains are involved in extensive protein–DNA and protein–protein interactions. The binding of strand-transfer inhibitors displaces the reactive viral DNA end from the active site, disarming the viral nucleoprotein complex. Our findings define the structural basis of retroviral DNA integration, and will allow modelling of the HIV-1 intasome to aid in the development of antiretroviral drugs.
Yves Pommier - One of the best experts on this subject based on the ideXlab platform.
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structure guided optimization of HIV Integrase strand transfer inhibitors
Journal of Medicinal Chemistry, 2017Co-Authors: Xue Zhi Zhao, Christophe Marchand, Yves Pommier, Peter Cherepanov, Steven J Smith, D P Maskell, Mathieu Metifiot, Valerie E Pye, Katherine FesenAbstract:Integrase mutations can reduce the effectiveness of the first-generation FDA-approved Integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogues of this scaffold. While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with t...
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HIV 1 Integrase strand transfer inhibitors with reduced susceptibility to drug resistant mutant Integrases
ACS Chemical Biology, 2016Co-Authors: Xue Zhi Zhao, Christophe Marchand, Yves Pommier, Peter Cherepanov, Steven J Smith, D P Maskell, Mathieu Metifiot, Valerie E Pye, Katherine Fesen, Stephen H HughesAbstract:HIV Integrase (IN) strand transfer inhibitors (INSTIs) are among the newest anti-AIDS drugs; however, mutant forms of IN can confer resistance. We developed noncytotoxic naphthyridine-containing INSTIs that retain low nanomolar IC50 values against HIV-1 variants harboring all of the major INSTI-resistant mutations. We found by analyzing crystal structures of inhibitors bound to the IN from the prototype foamy virus (PFV) that the most successful inhibitors show striking mimicry of the bound viral DNA prior to 3′-processing and the bound host DNA prior to strand transfer. Using this concept of “bi-substrate mimicry,” we developed a new broadly effective inhibitor that not only mimics aspects of both the bound target and viral DNA but also more completely fills the space they would normally occupy. Maximizing shape complementarity and recapitulating structural components encompassing both of the IN DNA substrates could serve as a guiding principle for the development of new INSTIs.
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probing chelation motifs in HIV Integrase inhibitors
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Arpita Agrawal, Yves Pommier, Kasthuraiah Maddali, Jamie Desoto, Jessica L Fullagar, Shahrzad Rostami, Douglas D Richman, Seth M CohenAbstract:A series of HIV Integrase (HIV-1 IN) inhibitors were synthesized to evaluate the role of the metal-binding group (MBG) in this class of metalloenzyme inhibitors. A total of 21 different raltegravir-chelator derivative (RCD) compounds were prepared that differed only in the nature of the MBG. These IN strand-transfer inhibitors (INSTIs) were evaluated in vitro in cell-free enzyme activity assays, and the in vitro results were further validated in cell culture experiments. All of the active compounds showed selective inhibition of the strand-transfer reaction over 3′-processing, suggesting a common mode of action with raltegravir. The results of the in vitro activity suggest that the nature of the MBG donor atoms, the overall MBG structure, and the specific arrangement of the MBG donor atom triad are essential for obtaining maximal HIV-1 IN inhibition. At least two compounds (RCD-4, RCD-5) containing a hydroxypyrone MBG were found to display superior strand-transfer inhibition when compared to an abbreviated analogue of raltegravir (RCD-1). By isolating and examining the role of the MBG in a series of INSTIs, we have identified a scaffold (hydroxypyrones) that may provide access to a unique class of HIV-1 IN inhibitors, and may help overcome rising raltegravir resistance.
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3 hydroxypyrimidine 2 4 diones as an inhibitor scaffold of HIV Integrase
Journal of Medicinal Chemistry, 2011Co-Authors: Jing Tang, Yves Pommier, Kasthuraiah Maddali, Robert Vince, Mathieu Metifiot, Yuk Y Sham, Zhengqiang WangAbstract:Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). Inhibitors with a novel structure core are essential for combating resistance associated with known IN inhibitors (INIs). We have previously disclosed a novel dual inhibitor scaffold of HIV IN and reverse transcriptase (RT). Here we report the complete structure−activity relationship (SAR), molecular modeling, and resistance profile of this inhibitor type on IN inhibition. These studies support an antiviral mechanism of dual inhibition against both IN and RT and validate 3-hydroxypyrimidine-2,4-diones as an IN inhibitor scaffold.
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Integrase inhibitors to treat HIV aids
Nature Reviews Drug Discovery, 2005Co-Authors: Yves Pommier, Allison A Johnson, Christophe MarchandAbstract:HIV Integrase is a rational target for treating HIV infection and preventing AIDS. It took approximately 12 years to develop clinically usable inhibitors of Integrase, and Phase I clinical trials of Integrase inhibitors have just begun. This review focuses on the molecular basis and rationale for developing Integrase inhibitors. The main classes of lead compounds are also described, as well as the concept of interfacial inhibitors of protein-nucleic-acid interactions that might apply to the clinically used strand-transfer inhibitors.
Vasu Nair - One of the best experts on this subject based on the ideXlab platform.
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a novel anti HIV active Integrase inhibitor with a favorable in vitro cytochrome p450 and uridine 5 diphospho glucuronosyltransferase metabolism profile
Antiviral Research, 2013Co-Authors: Maurice Okello, Roger G Ptak, Sanjay Mishra, Malik Nishonov, Marie K Mankowski, Julie Russell, Jiayi Wei, Priscilla A Hogan, Vasu NairAbstract:Research efforts on the human immunodeficiency virus (HIV) Integrase have resulted in two approved drugs. However, co-infection of HIV with Mycobacterium tuberculosis and other microbial and viral agents has introduced added complications to this pandemic, requiring favorable drug-drug interaction profiles for antiviral therapeutics targeting HIV. Cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) are pivotal determining factors in the occurrence of adverse drug-drug interactions. For this reason, it is important that anti-HIV agents, such as Integrase inhibitors, possess favorable profiles with respect to CYP and UGT. We have discovered a novel HIV Integrase inhibitor (compound 1) that exhibits low nM antiviral activity against a diverse set of HIV-1 isolates, and against HIV-2 and the simian immunodeficiency virus (SIV). Compound 1 displays low in vitro cytotoxicity and its resistance and related drug susceptibility profiles are favorable. Data from in vitro studies revealed that compound 1 was not a substrate for UGT isoforms and that it was not an inhibitor or activator of key CYP isozymes.
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discovery of a potent HIV Integrase inhibitor that leads to a prodrug with significant anti HIV activity
ACS Medicinal Chemistry Letters, 2011Co-Authors: Byung Seo, Guochen Chi, Maurice Okello, Sanjay Mishra, Malik Nishonov, Vinod Uchil, Qingning Shu, Vasu NairAbstract:Worldwide research efforts in drug discovery involving HIV Integrase have produced only one compound, raltegravir, that has been approved for clinical use in HIV/AIDS. As resistance, toxicity, and drug–drug interactions are recurring issues with all classes of anti-HIV drugs, the discovery of novel Integrase inhibitors remains a significant scientific challenge. We have designed a lead HIV-1 strand transfer (ST) inhibitor (IC50 70 nM), strategically assembled on a pyridinone scaffold. A focused structure–activity investigation of this parent compound led to a significantly more potent ST inhibitor, 2 (IC50 6 ± 3 nM). Compound 2 exhibits good stability in pooled human liver microsomes. It also displays a notably favorable profile with respect to key human cytochrome P450 (CYP) isozymes and human UDP glucuronosyl transferases (UGTs). The prodrug of inhibitor 2, i.e., compound 10, was found to possess remarkable anti-HIV-1 activity in cell culture (EC50 9 ± 4 nM, CC50 135 ± 7 μM, therapeutic index = 15 000).
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HIV Integrase inhibitors with nucleobase scaffolds discovery of a highly potent anti HIV agent
Journal of Medicinal Chemistry, 2006Co-Authors: Vasu Nair, Guochen Chi, Roger G Ptak, Nouri NeamatiAbstract:HIV Integrase is essential for HIV replication. However, there are currently no Integrase inhibitors in clinical use for AIDS. We have discovered a conceptually new β-diketo acid that is a powerful inhibitor of both the 3‘-processing and strand transfer steps of HIV-1 Integrase. The in vitro anti-HIV data of this inhibitor were remarkable as exemplified by its highly potent antiviral therapeutic efficacy against HIVTEKI and HIV-1NL4-3 replication in PBMC (TI >4,000 and >10,000, respectively).
Michael Rowley - One of the best experts on this subject based on the ideXlab platform.
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Quantitative prediction of human clearance guiding the development of raltegravir (MK-0518, Isentress) and related HIV Integrase inhibitors. Drug Metab. Dispos
2020Co-Authors: Ralph Laufer, Vincenzo Summa, Fabio Bonelli, Odalys Gonzalez Paz, Annalise Di Marco, Edith Monteagudo, Michael Rowley, Ph.d Ralph LauferAbstract:Abstract Human HIV Integrase inhibitors are a novel class of antiretroviral drugs that act by blocking incorporation of the proviral DNA into the host cell genome, a crucial step in the life cycle of HIV. In the present work, quantitative methods for prediction of human pharmacokinetics were used to guide the selection of development candidates from a series of dihydroxypyrimidine and N-methylpyrimidinone carboxamide inhibitors of HIV Integrase, which are cleared mainly by O-glucuronidation. The pharmacokinetics of 10 drugs from this series were determined in several preclinical species, including rats, dogs, rhesus monkeys and rabbits, and the in vitro turnover, plasma protein binding and blood to plasma partition ratio was studied using preparations from both preclinical species and humans. Two clearance prediction methods, based on physiologically based scaling or allometric scaling normalized for differences in microsomal turnover, were used to extrapolate human clearance. For three clinical candidates, including the novel AIDS drug raltegravir, oral drug exposure was predicted and compared to that observed in healthy human volunteers. Both scaling methods gave a reasonable correspondence between predicted and observed oral exposure. Prediction errors for the physiologically based method were less than 1.7-fold for 2 drugs, including raltegravir, and less than 3.5-fold for one drug. The exposures predicted using normalized allometric scaling were within
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Quantitative prediction of human clearance guiding the development of raltegravir (MK-0518, Isentress) and related HIV Integrase inhibitors. Drug Metab. Dispos
2020Co-Authors: Ralph Laufer, Vincenzo Summa, Fabio Bonelli, Odalys Gonzalez Paz, Annalise Di Marco, Edith Monteagudo, Michael RowleyAbstract:ABSTRACT: Human HIV Integrase inhibitors are a novel class of antiretroviral drugs that act by blocking incorporation of the proviral DNA into the host cell genome, a crucial step in the life cycle of HIV. In the present work, quantitative methods for prediction of human pharmacokinetics were used to guide the selection of development candidates from a series of dihydroxypyrimidine and N-methylpyrimidinone carboxamide inhibitors of HIV Integrase, which are cleared mainly by O-glucuronidation. The pharmacokinetics of 10 drugs from this series was determined in several preclinical species, including rats, dogs, rhesus monkeys, and rabbits, and the in vitro turnover, plasma protein binding, and blood/plasma partition ratio were studied using preparations from both preclinical species and humans. Two clearance prediction methods, based on physiologically based scaling or allometric scaling normalized for differences in microsomal turnover, were used to extrapolate human clearance. For three clinical candidates, including the novel AIDS drug raltegravir (MK-0518, Isentress), oral drug exposure was predicted and compared with that observed in healthy human volunteers. Both scaling methods gave a reasonable correspondence between predicted and observed oral exposure. Prediction errors for the physiologically based method were less than 1.7-fold for two drugs, including raltegravir, and less than 3.5-fold for one drug. The exposures predicted using normalized allometric scaling were within 1.1-to 1.5-fold of observed values for all three compounds. The accuracy of prediction by normalized allometric scaling was similar when using data from either four preclinical species or from rats and dogs only. The prediction methods used may be applicable to other drugs cleared predominantly by glucuronidation. HIV-1 is responsible for AIDS, one of the most urgent world health threats. Currently approved therapies are based on inhibitors of HIV protease, reverse transcriptase, and viral entry The currently used approaches for predicting human clearance of drugs fall into three major classes, physiologically based scaling (PBS) models, allometric scaling, and allometric scaling of in vivo clearance normalized by in vitro clearance data [normalized allometric scaling (NAS)]. In the PBS method, in vitro turnover in liver microsomes or hepatocytes is used to estimate intrinsic clearance for the whole liver by the use of a scaling factor and, subsequently, hepatic clearance (CL h ) with the use of a physiologic liver mode
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dihydroxypyrimidine 4 carboxamides as novel potent and selective HIV Integrase inhibitors
Journal of Medicinal Chemistry, 2007Co-Authors: Paola Pace, Alessia Petrocchi, Cristina Gardelli, Emilia M Di Francesco, Steven J Harper, Ester Muraglia, Emanuela Nizi, Federica Orvieto, Marco Poma, Michael RowleyAbstract:Human immunodeficiency virus type-1 (HIV-1) Integrase, one of the three constitutive viral enzymes required for replication, is a rational target for chemotherapeutic intervention in the treatment of AIDS that has also recently been confirmed in the clinical setting. We report here on the design and synthesis of N-benzyl-5,6-dihydroxypyrimidine-4-carboxamides as a class of agents which exhibits potent inhibition of the HIV-Integrase-catalyzed strand transfer process. In the current study, structural modifications on these molecules were made in order to examine effects on HIV-Integrase inhibitory potencies. One of the most interesting compounds for this series is 2-[1-(dimethylamino)-1-methylethyl]-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide 38, with a CIC95 of 78 nM in the cell-based assay in the presence of serum proteins. The compound has favorable pharmacokinetic properties in preclinical species (rats, dogs, and monkeys) and shows no liabilities in several counterscreening assays, highli...
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4 5 dihydroxypyrimidine carboxamides and n alkyl 5 hydroxypyrimidinone carboxamides are potent selective HIV Integrase inhibitors with good pharmacokinetic profiles in preclinical species
Journal of Medicinal Chemistry, 2006Co-Authors: Vincenzo Summa, Alessia Petrocchi, Cristina Gardelli, Odalys Gonzalez Paz, Ralph Laufer, Edith Monteagudo, Michael Rowley, Ester Muraglia, Victor G Matassa, Paola PaceAbstract:The dihydroxypyrimidine carboxamide 4a was discovered as a potent and selective HIV Integrase strand transfer inhibitor. The optimization of physicochemical properties, pharmacokinetic profiles, and potency led to the identification of 13 in the dihydroxypyrimidine series and 18 in the N-methylpyrimidinone series having low nanomolar activity in the cellular HIV spread assay in the presence of 50% normal human serum and very good pharmacokinetics in preclinical species.
Alan Engelman - One of the best experts on this subject based on the ideXlab platform.
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structural basis of second generation HIV Integrase inhibitor action and viral resistance
Science, 2020Co-Authors: Nicola J Cook, Denes Berta, Magd Badaoui, Allison Ballandrascolas, Andrea Nans, A Kotecha, Edina Rosta, Alan Engelman, Peter CherepanovAbstract:Although second-generation HIV Integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in Integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics.
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multifaceted HIV Integrase functionalities and therapeutic strategies for their inhibition
Journal of Biological Chemistry, 2019Co-Authors: Alan EngelmanAbstract:Antiretroviral inhibitors that are used to manage HIV infection/AIDS predominantly target three enzymes required for virus replication: reverse transcriptase, protease, and Integrase. Although Integrase inhibitors were the last among this group to be approved for treating people living with HIV, they have since risen to the forefront of treatment options. Integrase strand transfer inhibitors (INSTIs) are now recommended components of frontline and drug-switch antiretroviral therapy formulations. Integrase catalyzes two successive magnesium-dependent polynucleotidyl transferase reactions, 3′ processing and strand transfer, and INSTIs tightly bind the divalent metal ions and viral DNA end after 3′ processing, displacing from the Integrase active site the DNA 3′-hydroxyl group that is required for strand transfer activity. Although second-generation INSTIs present higher barriers to the development of viral drug resistance than first-generation compounds, the mechanisms underlying these superior barrier profiles are incompletely understood. A separate class of HIV-1 Integrase inhibitors, the allosteric Integrase inhibitors (ALLINIs), engage Integrase distal from the enzyme active site, namely at the binding site for the cellular cofactor lens epithelium-derived growth factor (LEDGF)/p75 that helps to guide integration into host genes. ALLINIs inhibit HIV-1 replication by inducing Integrase hypermultimerization, which precludes Integrase binding to genomic RNA and perturbs the morphogenesis of new viral particles. Although not yet approved for human use, ALLINIs provide important probes that can be used to investigate the link between HIV-1 Integrase and viral particle morphogenesis. Herein, I review the mechanisms of retroviral integration as well as the promises and challenges of using Integrase inhibitors for HIV/AIDS management.
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retroviral intasome assembly and inhibition of dna strand transfer
Nature, 2010Co-Authors: Stephen Hare, Alan Engelman, S S Gupta, Eugene Valkov, Peter CherepanovAbstract:Integrase is an essential retroviral enzyme that binds both termini of linear viral DNA and inserts them into a host cell chromosome. The structure of full-length retroviral Integrase, either separately or in complex with DNA, has been lacking. Furthermore, although clinically useful inhibitors of HIV Integrase have been developed, their mechanism of action remains speculative. Here we present a crystal structure of full-length Integrase from the prototype foamy virus in complex with its cognate DNA. The structure shows the organization of the retroviral intasome comprising an Integrase tetramer tightly associated with a pair of viral DNA ends. All three canonical Integrase structural domains are involved in extensive protein–DNA and protein–protein interactions. The binding of strand-transfer inhibitors displaces the reactive viral DNA end from the active site, disarming the viral nucleoprotein complex. Our findings define the structural basis of retroviral DNA integration, and will allow modelling of the HIV-1 intasome to aid in the development of antiretroviral drugs.
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characterization of a replication competent Integrase defective human immunodeficiency virus HIV simian virus 40 chimera as a powerful tool for the discovery and validation of HIV Integrase inhibitors
Journal of Virology, 2007Co-Authors: Dirk Daelemans, Erik De Clercq, Alan EngelmanAbstract:Integrase is actively studied as an antiviral target, but many inhibitors selected from biochemical screens fail to inhibit human immunodeficiency virus (HIV) replication or primarily affect off-site targets. Here we develop and validate a replication-competent, simian virus 40-HIV Integrase mutant chimera as a novel tool to classify the mechanism of action of potential Integrase inhibitors. Whereas the mutant was more susceptible than the wild type to entry, reverse transcriptase, and protease inhibitors, it specifically resisted the action of Integrase inhibitor L-870,810. We furthermore demonstrate inhibition of integration by GS-9137 and GS-9160 and off-site targeting by the 6-aminoquinolone antibiotic WM-5.
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crystal structure of the catalytic domain of HIV 1 Integrase similarity to other polynucleotidyl transferases
Science, 1994Co-Authors: Fred Dyda, Robert Craigie, Alan Engelman, Alison B Hickman, Timothy M Jenkins, David R DaviesAbstract:HIV Integrase is the enzyme responsible for inserting the viral DNA into the host chromosome; it is essential for HIV replication. The crystal structure of the catalytically active core domain (residues 50 to 212) of HIV-1 Integrase was determined at 2.5 A resolution. The central feature of the structure is a five-stranded beta sheet flanked by helical regions. The overall topology reveals that this domain of Integrase belongs to a superfamily of polynucleotidyl transferases that includes ribonuclease H and the Holliday junction resolvase RuvC. The active site region is identified by the position of two of the conserved carboxylate residues essential for catalysis, which are located at similar positions in ribonuclease H. In the crystal, two molecules form a dimer with a extensive solvent-inaccessible interface of 1300 A2 per monomer.