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Review

In Search of Second-Generation HIV Integrase Inhibitors: Targeting Integration Beyond Strand Transfer

, , &
Pages 1259-1274 | Published online: 21 Oct 2009

Bibliography

  • Greene WC , PeterlinBM. Charting HIV’s remarkable voyage through the cell: basic science as a passport to future therapy.Nat. Med.8(7), 673–680 (2002).
  • Gomez C , HopeTJ. The ins and outs of HIV replication.Cell Microbiol.7(5), 621–626 (2005).
  • Tozser J . Stages of HIV replication and targets for therapeutic intervention.Curr. Top. Med. Chem.3(13), 1447–1457 (2003).
  • Christ F , ThysW, De Rijck J et al. Transportin-SR2 imports HIV into the nucleus. Curr. Biol.18(16), 1192–1202 (2008).
  • Alexaki A , LiuY, WigdahlB. Cellular reservoirs of HIV-1 and their role in viral persistence.Curr. HIV Res.6(5), 388–400 (2008).
  • Gulick RM , MellorsJW, HavlirDet al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N. Engl. J. Med. 337(11), 734–739 (1997).
  • Hammer SM , SquiresKE, HughesMDet al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N. Engl. J. Med. 337(11), 725–733 (1997).
  • Wilson LE , GallantJE. HIV/AIDS: the management of treatment-experienced HIV-infected patients: new drugs and drug combinations.Clin. Infect. Dis.48(2), 214–221 (2009).
  • Bailey AC , FisherM. Current use of antiretroviral treatment.Br. Med. Bull.87, 175–192 (2008).
  • Coffin JM . HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science267(5197), 483–489 (1995).
  • Wei X , GhoshSK, TaylorMEet al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373(6510), 117–122 (1995).
  • Kulkosky J , SkalkaAM. Molecular mechanism of retroviral DNA integration.Pharmacol. Ther.61(1–2), 185–203 (1994).
  • Bushman FD , CraigieR. Activities of human immunodeficiency virus (HIV) integration protein in vitro: specific cleavage and integration of HIV DNA.Proc. Natl Acad. Sci. USA88(4), 1339–1343 (1991).
  • Gerton JL , HerschlagD, BrownPO. Stereospecificity of reactions catalyzed by HIV-1 integrase.J. Biol. Chem.274(47), 33480–33487 (1999).
  • Engelman A , MizuuchiK, CraigieR. HIV-1 DNA integration: mechanism of viral DNA cleavage and DNA strand transfer.Cell67(6), 1211–1221 (1991).
  • Albanese A , ArosioD, TerreniM, CeresetoA. HIV-1 pre-integration complexes selectively target decondensed chromatin in the nuclear periphery.PLoS ONE3(6), E2413 (2008).
  • Maertens G , CherepanovP, PluymersWet al. LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. J. Biol. Chem. 278(35), 33528–33539 (2003).
  • Ciuffi A . Mechanisms governing lentivirus integration site selection.Curr. Gene Ther.8(6), 419–429 (2008).
  • McKee CJ , KesslJJ, ShkriabaiN, DarMJ, EngelmanA, KvaratskheliaM. Dynamic modulation of HIV-1 integrase structure and function by cellular lens epithelium-derived growth factor (LEDGF) protein.J. Biol. Chem.283(46), 31802–31812 (2008).
  • Poeschla EM . Integrase, LEDGF/p75 and HIV replication.Cell Mol. Life Sci.65(9), 1403–1424 (2008).
  • Botbol Y , RaghavendraNK, RahmanS, EngelmanA, LavigneM. Chromatinized templates reveal the requirement for the LEDGF/p75 PWWP domain during HIV-1 integration in vitro.Nucleic Acids Res.36(4), 1237–1246 (2008).
  • Shun MC , BotbolY, LiXet al. Identification and characterization of PWWP domain residues critical for LEDGF/p75 chromatin binding and human immunodeficiency virus type 1 infectivity. J. Virol. 82(23), 11555–11567 (2008).
  • Hombrouck A , De RijckJ, HendrixJet al. Virus evolution reveals an exclusive role for LEDGF/p75 in chromosomal tethering of HIV. PLoS Pathog.3(3), e47 (2007).
  • Pandey KK , SinhaS, GrandgenettDP. Transcriptional coactivator LEDGF/p75 modulates human immunodeficiency virus type 1 integrase-mediated concerted integration.J. Virol.81(8), 3969–3979 (2007).
  • Marshall HM , RonenK, BerryCet al. Role of PSIP1/LEDGF/p75 in lentiviral infectivity and integration targeting. PLoS ONE 2(12), E1340 (2007).
  • Vandekerckhove L , ChristF, Van Maele B et al. Transient and stable knockdown of the integrase cofactor LEDGF/p75 reveals its role in the replication cycle of human immunodeficiency virus. J. Virol.80(4), 1886–1896 (2006).
  • Vandegraaff N , DevroeE, TurlureF, SilverPA, EngelmanA. Biochemical and genetic analyses of integrase-interacting proteins lens epithelium-derived growth factor (LEDGF)/p75 and hepatoma-derived growth factor related protein 2 (HRP2) in preintegration complex function and HIV-1 replication. Virology346(2), 415–426 (2006).
  • Llano M , VanegasM, HutchinsN, ThompsonD, DelgadoS, PoeschlaEM. Identification and characterization of the chromatin-binding domains of the HIV-1 integrase interactor LEDGF/p75.J. Mol. Biol.360(4), 760–773 (2006).
  • Llano M , SaenzDT, MeehanAet al. An essential role for LEDGF/p75 in HIV integration. Science 314(5798), 461–464 (2006).
  • Yoder KE , BushmanFD. Repair of gaps in retroviral DNA integration intermediates.J. Virol.74(23), 11191–11200 (2000).
  • Engelman A , BushmanFD, CraigieR. Identification of discrete functional domains of HIV-1 integrase and their organization within an active multimeric complex.EMBO J.12(8), 3269–3275 (1993).
  • Bushman FD , EngelmanA, PalmerI, WingfieldP, CraigieR. Domains of the integrase protein of human immunodeficiency virus type 1 responsible for polynucleotidyl transfer and zinc binding.Proc. Natl Acad. Sci. USA90(8), 3428–3432 (1993).
  • van Gent DC , VinkC, GroenegerAA, PlasterkRH. Complementation between HIV integrase proteins mutated in different domains.EMBO J.12(8), 3261–3267 (1993).
  • Andrake MD , SkalkaAM. Retroviral integrase, putting the pieces together.J. Biol. Chem.271(33), 19633–19636 (1996).
  • Vink C , Oude Groeneger AM, Plasterk RH. Identification of the catalytic and DNA-binding region of the human immunodeficiency virus type I integrase protein. Nucleic Acids Res.21(6), 1419–1425 (1993).
  • Asante-Appiah E , SeeholzerSH, SkalkaAM. Structural determinants of metal-induced conformational changes in HIV-1 integrase.J. Biol. Chem.273(52), 35078–35087 (1998).
  • Asante-Appiah E , SkalkaAM. A metal-induced conformational change and activation of HIV-1 integrase.J. Biol. Chem.272(26), 16196–16205 (1997).
  • Gerton JL , OhgiS, OlsenM, DeRisiJ, BrownPO. Effects of mutations in residues near the active site of human immunodeficiency virus type 1 integrase on specific enzyme-substrate interactions.J. Virol.72(6), 5046–5055 (1998).
  • Chen Z , YanY, MunshiSet al. X-ray structure of simian immunodeficiency virus integrase containing the core and C-terminal domain (residues 50–293) – an initial glance of the viral DNA binding platform. J. Mol. Biol. 296(2), 521–533 (2000).
  • Yang ZN , MueserTC, BushmanFD, HydeCC. Crystal structure of an active two-domain derivative of Rous sarcoma virus integrase.J. Mol. Biol.296(2), 535–548 (2000).
  • Steiniger-White M , BhasinA, LovellS, RaymentI, ReznikoffWS. Evidence for ‘unseen’ transposase–DNA contacts.J. Mol. Biol.322(5), 971–982 (2002).
  • Wang JY , LingH, YangW, CraigieR. Structure of a two-domain fragment of HIV-1 integrase: implications for domain organization in the intact protein.EMBO J.20(24), 7333–7343 (2001).
  • Chen JC , KrucinskiJ, MierckeLJet al. Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: a model for viral DNA binding. Proc. Natl Acad. Sci. USA 97(15), 8233–8238 (2000).
  • Michel F , CrucifixC, GrangerFet al. Structural basis for HIV-1 DNA integration in the human genome, role of the LEDGF/P75 cofactor. EMBO J. 28(7), 980–991 (2009).
  • Ren G , GaoK, BushmanFD, YeagerM. Single-particle image reconstruction of a tetramer of HIV integrase bound to DNA.J. Mol. Biol.366(1), 286–294 (2007).
  • Thys W , BusschotsK, McNeelyM, VoetA, ChristF, DebyserZ. LEDGF/p75 and transportin-SR2 are cellular cofactors of HIV integrase and novel targets for antiviral therapy.Future Med.3(2), 171–188 (2009).
  • Grant P , ZolopaA. Integrase inhibitors: a clinical review of raltegravir and elvitegravir.J. HIV Ther.13(2), 36–39 (2008).
  • De Clercq E . New developments in anti-HIV chemotherapy.Curr. Med. Chem.8(13), 1543–1572 (2001).
  • Neamati N , MarchandC, PommierY. HIV-1 integrase inhibitors: past, present, and future.Adv. Pharmacol.49, 147–165 (2000).
  • Lin Z , NeamatiN, ZhaoHet al. Chicoric acid analogues as HIV-1 integrase inhibitors. J. Med. Chem. 42(8), 1401–1414 (1999).
  • Cherepanov P , EsteJA, RandoRFet al. Mode of interaction of G-quartets with the integrase of human immunodeficiency virus type 1. Mol. Pharmacol. 52(5), 771–780 (1997).
  • Pluymers W , NeamatiN, PannecouqueCet al. Viral entry as the primary target for the anti-HIV activity of chicoric acid and its tetra-acetyl esters. Mol. Pharmacol. 58(3), 641–648 (2000).
  • Mazumder A , NeamatiN, OjwangJO, SunderS, RandoRF, PommierY. Inhibition of the human immunodeficiency virus type 1 integrase by guanosine quartet structures.Biochemistry35(43), 13762–13771 (1996).
  • Marchand C , ZhangX, PaisGCet al. Structural determinants for HIV-1 integrase inhibition by β-diketo acids. J. Biol. Chem. 277(15), 12596–12603 (2002).
  • Barreca ML , De Luca L, Iraci N, Chimirri A. Binding mode prediction of strand transfer HIV-1 integrase inhibitors using Tn5 transposase as a plausible surrogate model for HIV-1 integrase. J. Med. Chem.49(13), 3994–3997 (2006).
  • Barreca ML , OrtusoF, IraciN, De Luca L, Alcaro S, Chimirri A. Tn5 transposase as a useful platform to simulate HIV-1 integrase inhibitor binding mode. Biochem. Biophys. Res. Commun.363(3), 554–560 (2007).
  • Ferro S , De LucaL, BarrecaMLet al. Docking studies on a new human immunodeficiency virus integrase-Mg-DNA complex: phenyl ring exploration and synthesis of 1H-benzylindole derivatives through fluorine substitutions. J. Med. Chem.52(2), 569–573 (2009).
  • Hazuda DJ , FelockP, WitmerMet al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287(5453), 646–650 (2000).
  • Zhao G , WangC, LiuC, LouH. New developments in diketo-containing inhibitors of HIV-1 integrase.Mini Rev. Med. Chem.7(7), 707–725 (2007).
  • Hazuda DJ , AnthonyNJ, GomezRPet al. A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase. Proc. Natl Acad. Sci. USA 101(31), 11233–11238 (2004).
  • Pace P , SpieserSA, SummaV. 4-hydroxy-5-pyrrolinone-3-carboxamide HIV-1 integrase inhibitors.Bioorg. Med. Chem. Lett.18(14), 3865–3869 (2008).
  • Muraglia E , KinzelO, GardelliCet al. Design and synthesis of bicyclic pyrimidinones as potent and orally bioavailable HIV-1 integrase inhibitors. J. Med. Chem. 51(4), 861–874 (2008).
  • Jin H , CaiRZ, SchachererLet al. Design, synthesis, and SAR studies of novel and highly active tri-cyclic HIV integrase inhibitors. Bioorg. Med. Chem. Lett. 16(15), 3989–3992 (2006).
  • Summa V , PetrocchiA, BonelliFet al. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J. Med. Chem. 51(18), 5843–5855 (2008).
  • Serrao E , OddeS, RamkumarK, NeamatiN. Raltegravir, elvitegravir, and metoogravir: the birth of ‘me-too’ HIV-1 integrase inhibitors.Retrovirology6, 25 (2009).
  • Al-Mawsawi LQ , Al-SafiRI, NeamatiN. Anti-infectives: clinical progress of HIV-1 integrase inhibitors.Expert Opin. Emerg. Drugs13(2), 213–225 (2008).
  • Shimura K , KodamaE, SakagamiYet al. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J. Virol.82(2), 764–774 (2008).
  • Kobayashi M , NakaharaK, SekiTet al. Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants. Antiviral Res. 80(2), 213–222 (2008).
  • Roquebert B , DamondF, CollinGet al. HIV-2 integrase gene polymorphism and phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitors raltegravir and elvitegravir in vitro. J. Antimicrob. Chemother. 62(5), 914–920 (2008).
  • Barreca ML , FerroS, RaoAet al. Pharmacophore-based design of HIV-1 integrase strand-transfer inhibitors. J. Med. Chem 48(22), 7084–7088 (2005).
  • Pannecouque C , PluymersW, Van Maele B et al. New class of HIV integrase inhibitors that block viral replication in cell culture. Curr. Biol.12(14), 1169–1177 (2002).
  • Hombrouck A , HantsonA, van Remoortel B et al. Selection of human immunodeficiency virus type 1 resistance against the pyranodipyrimidine V-165 points to a multimodal mechanism of action. J. Antimicrob. Chemother.59(6), 1084–1095 (2007).
  • Mekouar K , MouscadetJF, DesmaeleDet al. Styrylquinoline derivatives: a new class of potent HIV-1 integrase inhibitors that block HIV-1 replication in CEM cells. J. Med. Chem. 41(15), 2846–2857 (1998).
  • Bonnenfant S , ThomasCM, VitaCet al. Styrylquinolines, integrase inhibitors acting prior to integration: a new mechanism of action for anti-integrase agents. J. Virol. 78(11), 5728–5736 (2004).
  • Deprez E , BarbeS, KolaskiMet al. Mechanism of HIV-1 integrase inhibition by styrylquinoline derivatives in vitro. Mol. Pharmacol. 65(1), 85–98 (2004).
  • Mousnier A , LehH, MouscadetJF, DargemontC. Nuclear import of HIV-1 integrase is inhibited in vitro by styrylquinoline derivatives. Mol. Pharmacol.66(4), 783–788 (2004).
  • Tintori C , ManettiF, VeljkovicNet al. Novel virtual screening protocol based on the combined use of molecular modeling and electron-ion interaction potential techniques to design HIV-1 integrase inhibitors. J. Chem. Inf. Model 47(4), 1536–1544 (2007).
  • Pasquini S , MugnainiC, TintoriCet al. Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors. J. Med. Chem. 51(16), 5125–5129 (2008).
  • Brodin P , PinskayaM, VolkovEet al. Branched oligonucleotide-intercalator conjugate forming a parallel stranded structure inhibits HIV-1 integrase. FEBS Lett. 460(2), 270–274 (1999).
  • Fesen MR , KohnKW, LeteurtreF, PommierY. Inhibitors of human immunodeficiency virus integrase.Proc. Natl Acad. Sci. USA90(6), 2399–2403 (1993).
  • Carteau S , MouscadetJF, GoulaouicH, SubraF, AuclairC. Effect of topoisomerase inhibitors on the in vitro HIV DNA integration reaction.Biochem. Biophys. Res. Commun.192(3), 1409–1414 (1993).
  • Luck G , ZimmerC, ReinertKE, ArcamoneF. Specific interactions of distamycin A and its analogs with (A-T) rich and (G-C) rich duplex regions of DNA and deoxypolynucleotides.Nucleic Acids Res.4(8), 2655–2670 (1977).
  • Kopka ML , YoonC, GoodsellD, PjuraP, DickersonRE. Binding of an antitumor drug to DNA, netropsin and C-G-C-G-A-A-T-T-BrC-G-C-G.J. Mol. Biol.183(4), 553–563 (1985).
  • Kopka ML , YoonC, GoodsellD, PjuraP, DickersonRE. The molecular origin of DNA-drug specificity in netropsin and distamycin.Proc. Natl Acad. Sci. USA82(5), 1376–1380 (1985).
  • Lown JW . Lexitropsins: rational design of DNA sequence reading agents as novel anti-cancer agents and potential cellular probes.Anticancer Drug Des.3(1), 25–40 (1988).
  • Neamati N , MazumderA, SunderSet al. Highly potent synthetic polyamides, bisdistamycins, and lexitropsins as inhibitors of human immunodeficiency virus type 1 integrase. Mol. Pharmacol. 54(2), 280–290 (1998).
  • Spitzer GM , WellenzohnB, LaggnerC, LangerT, LiedlKR. DNA minor groove pharmacophores describing sequence specific properties.J. Chem. Inf. Model47(4), 1580–1589 (2007).
  • Spitzer GM , WellenzohnB, MarktP, KirchmairJ, LangerT, LiedlKR. Hydrogen-bonding patterns of minor groove-binder-DNA complexes reveal criteria for discovery of new scaffolds.J. Chem. Inf. Model49(4), 1063–1069 (2009).
  • Berthoux L , SebastianS, MuesingMA, LubanJ. The role of lysine 186 in HIV-1 integrase multimerization.Virology364(1), 227–236 (2007).
  • Kalpana GV , ReicinA, ChengGS, SorinM, PaikS, GoffSP. Isolation and characterization of an oligomerization-negative mutant of HIV-1 integrase.Virology259(2), 274–285 (1999).
  • Puras Lutzke RA , EppensNA, WeberPA, HoughtenRA, PlasterkRH. Identification of a hexapeptide inhibitor of the human immunodeficiency virus integrase protein by using a combinatorial chemical library.Proc. Natl Acad. Sci. USA92(25), 11456–11460 (1995).
  • Sourgen F , MarounRG, FrereVet al. A synthetic peptide from the human immunodeficiency virus type-1 integrase exhibits coiled-coil properties and interferes with the in vitro integration activity of the enzyme. Correlated biochemical and spectroscopic results. Eur. J. Biochem. 240(3), 765–773 (1996).
  • Maroun RG , GayetS, BenleulmiMSet al. Peptide inhibitors of HIV-1 integrase dissociate the enzyme oligomers. Biochemistry 40(46), 13840–13848 (2001).
  • Zhao L , O‘ReillyMK, ShultzMD, ChmielewskiJ. Interfacial peptide inhibitors of HIV-1 integrase activity and dimerization.Bioorg. Med. Chem. Lett.13(6), 1175–1177 (2003).
  • Hu JP , GongXQ, SuJG, ChenWZ, WangCX. Study on the molecular mechanism of inhibiting HIV-1 integrase by EBR28 peptide via molecular modeling approach.Biophys. Chem.132(2–3), 69–80 (2008).
  • Krajewski K , MarchandC, LongYQ, PommierY, RollerPP. Synthesis and HIV-1 integrase inhibitory activity of dimeric and tetrameric analogs of indolicidin.Bioorg. Med. Chem. Lett.14(22), 5595–5598 (2004).
  • Desjobert C , de SoultraitVR, FaureAet al. Identification by phage display selection of a short peptide able to inhibit only the strand transfer reaction catalyzed by human immunodeficiency virus type 1 integrase. Biochemistry43(41), 13097–13105 (2004).
  • Krajewski K , LongYQ, MarchandC, PommierY, RollerPP. Design and synthesis of dimeric HIV-1 integrase inhibitory peptides.Bioorg. Med. Chem. Lett.13(19), 3203–3205 (2003).
  • Singh SB , HerathK, GuanZet al. Integramides A and B, two novel non-ribosomal linear peptides containing nine C(a)-methyl amino acids produced by fungal fermentations that are inhibitors of HIV-1 integrase. Org. Lett. 4(9), 1431–1434 (2002).
  • Fermandjian S , MarounRS, AmekrazB, JankowskiCK. Self-association of an amphipathic helix peptide inhibitor of HIV-1 integrase assessed by electro spray ionization mass spectrometry in trifluoroethanol/water mixtures.Rapid Commun. Mass Spectrom.15(5), 320–324 (2001).
  • Krebs D , MarounRG, SourgenF, TroalenF, DavoustD, FermandjianS. Helical and coiled-coil-forming properties of peptides derived from and inhibiting human immunodeficiency virus type 1 integrase assessed by 1H-NMR – use of NH temperature coefficients to probe coiled-coil structures.Eur. J. Biochem.253(1), 236–244 (1998).
  • Fry DC . Drug-like inhibitors of protein-protein interactions: a structural examination of effective protein mimicry.Curr. Protein Pept. Sci.9(3), 240–247 (2008).
  • Zutshi R , ChmielewskiJ. Targeting the dimerization interface for irreversible inhibition of HIV-1 protease.Bioorg. Med. Chem. Lett.10(17), 1901–1903 (2000).
  • He MM , SmithAS, OslobJDet al. Small-molecule inhibition of TNF-α. Science 310(5750), 1022–1025 (2005).
  • Alzani R , CozziE, CortiAet al. Mechanism of suramin-induced deoligomerization of tumor necrosis factor alpha. Biochemistry 34(19), 6344–6350 (1995).
  • Symons KT , MassariME, NguyenPMet al. KLYP956 is a non-imidazole-based orally active inhibitor of nitric oxide synthase dimerization. Mol. Pharmacol. DOI: 10.1124/mol.109.055434 (2009) (Epub ahead of print).
  • McMillan K , AdlerM, AuldDSet al. Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry. Proc. Natl Acad. Sci. USA 97(4), 1506–1511 (2000).
  • Morozov A , YungE, KalpanaGV. Structure–function analysis of integrase interactor 1/hSNF5L1 reveals differential properties of two repeat motifs present in the highly conserved region.Proc. Natl Acad. Sci. USA95(3), 1120–1125 (1998).
  • Li L , YoderK, HansenMSet al. Retroviral cDNA integration: stimulation by HMG I family proteins. J. Virol. 74(23), 10965–10974 (2000).
  • Lin CW , EngelmanA. The barrier-to-autointegration factor is a component of functional human immunodeficiency virus type 1 preintegration complexes.J. Virol.77(8), 5030–5036 (2003).
  • Van Maele B , BusschotsK, VandekerckhoveL, ChristF, DebyserZ. Cellular co-factors of HIV-1 integration.Trends Biochem. Sci.31(2), 98–105 (2006).
  • De Rijck J , VandekerckhoveL, GijsbersRet al. Overexpression of the lens epithelium-derived growth factor/p75 integrase binding domain inhibits human immunodeficiency virus replication. J. Virol. 80(23), 11498–11509 (2006).
  • Emiliani S , MousnierA, BusschotsKet al. Integrase mutants defective for interaction with LEDGF/p75 are impaired in chromosome tethering and HIV-1 replication. J. Biol. Chem. 280(27), 25517–25523 (2005).
  • Shun MC , RaghavendraNK, VandegraaffNet al. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev. 21(14), 1767–1778 (2007).
  • Cherepanov P , MaertensG, ProostPet al. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J. Biol. Chem. 278(1), 372–381 (2003).
  • Ge H , SiY, RoederRG. Isolation of cDNAs encoding novel transcription coactivators p52 and p75 reveals an alternate regulatory mechanism of transcriptional activation.EMBO J.17(22), 6723–6729 (1998).
  • Singh DP , KimuraA, ChylackLT Jr, Shinohara T. Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing. Gene242(1–2), 265–273 (2000).
  • Singh DP , FatmaN, KimuraA, ChylackLT Jr, Shinohara T. LEDGF binds to heat shock and stress-related element to activate the expression of stress-related genes. Biochem. Biophys. Res. Commun.283(4), 943–955 (2001).
  • Nguyen TA , BoyleDL, WagnerLM, ShinoharaT, TakemotoDJ. LEDGF activation of PKC gamma and gap junction disassembly in lens epithelial cells.Exp. Eye Res.76(5), 565–572 (2003).
  • Chylack LT Jr, Fu L, Mancini R et al. Lens epithelium-derived growth factor (LEDGF/p75) expression in fetal and adult human brain. Exp. Eye Res.79(6), 941–948 (2004).
  • Sutherland HG , NewtonK, BrownsteinDGet al. Disruption of LEDGF/Psip1 results in perinatal mortality and homeotic skeletal transformations. Mol. Cell Biol. 26(19), 7201–7210 (2006).
  • Ahuja HG , HongJ, AplanPD, TcheurekdjianL, FormanSJ, SlovakML. t(9;11)(p22;p15) in acute myeloid leukemia results in a fusion between NUP98 and the gene encoding transcriptional coactivators p52 and p75-lens epithelium-derived growth factor (LEDGF).Cancer Res.60(22), 6227–6229 (2000).
  • Daniels T , ZhangJ, GutierrezIet al. Antinuclear autoantibodies in prostate cancer: immunity to LEDGF/p75, a survival protein highly expressed in prostate tumors and cleaved during apoptosis. Prostate 62(1), 14–26 (2005).
  • Huang TS , MyklebustLM, KjarlandEet al. LEDGF/p75 has increased expression in blasts from chemotherapy-resistant human acute myelogenic leukemia patients and protects leukemia cells from apoptosis in vitro. Mol. Cancer 6, 31 (2007).
  • Brown-Bryan TA , LeohLS, GanapathyVet al. Alternative splicing and caspase-mediated cleavage generate antagonistic variants of the stress oncoprotein LEDGF/p75. Mol. Cancer Res. 6(8), 1293–1307 (2008).
  • Busschots K , VercammenJ, EmilianiSet al. The interaction of LEDGF/p75 with integrase is lentivirus-specific and promotes DNA binding. J. Biol. Chem. 280(18), 17841–17847 (2005).
  • Busschots K , VoetA, De Maeyer M et al. Identification of the LEDGF/p75 binding site in HIV-1 integrase. J. Mol. Biol.365(5), 1480–1492 (2007).
  • Cherepanov P , SunZY, RahmanS, MaertensG, WagnerG, EngelmanA. Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75.Nat. Struct. Mol. Biol.12(6), 526–532 (2005).
  • Cherepanov P , AmbrosioAL, RahmanS, EllenbergerT, EngelmanA. Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75.Proc. Natl Acad. Sci. USA102(48), 17308–17313 (2005).
  • Du L , ZhaoY, ChenJet al. D77, one benzoic acid derivative, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular LEDGF/p75. Biochem. Biophys. Res. Commun. 375(1), 139–144 (2008).
  • Hou Y , McGuinnessDE, ProngayAJet al. Screening for antiviral inhibitors of the HIV integrase-LEDGF/p75 interaction using the AlphaScreen™ luminescent proximity assay. J. Biomol. Screen 13(5), 406–414 (2008).
  • Debyser Z . Cellular co-factors of HIV integrase – from target identification to drug discovery. Presented at: 16th Conference on Retroviruses and Opportunistic Infections. Montreal, Canada, 8–11 February 2009.
  • Benarous R , BarbeyS, SimonAet al. Identification of anti-retroviral compounds active on viruses resistant to raltegravir and that inhibit HIV-1 integration despite the absence of effect on the catalytic activity of integrase. Presented at: 16th Conference on Retroviruses and Opportunistic Infections. Montreal, Canada, 8–11 February 2009.
  • Malet I , DelelisO, ValantinMAet al. Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob. Agents Chemother. 52(4), 1351–1358 (2008).
  • Billich A . S-1360 Shionogi-GlaxoSmithKline.Curr. Opin. Investig. Drugs4(2), 206–209 (2003).
  • Vacca J , WaiJ, FisherTet al. Discovery of MK-2048: subtle changes confer unique resistance properties to a series of tricyclic hydroxypyrrole integrase strand transfer inhibitors. Presented at: 4th International AIDS Society (IAS) Conference. Sydney, Australia, 2007.

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