Erratum: Inhibiting the HIV integration process: Past, present, and the future (Journal of Medicinal Chemistry (2014) 57 (539-566) DOI: 10.1021/jm400674a);Inhibiting the HIV integration process: Past, present, and the future

Journal of Medicinal Chemistry

Volumn 57, Issue 3, 2014, Pages 539-566

  Di Santo, Roberto ^a  

^a SAPIENZA UNIVERSITY OF ROME   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

2 (QUINOLIN 3 YL)ACETIC ACID; ATORVASTATIN; BENZOIC ACID DERIVATIVE; CARBIDOPA; CHIBA 3002; CHIBA 3053; CX 014442; CX 0516; CX 14442; DARUNAVIR; DNAZYME; DOLUTEGRAVIR; ELVITEGRAVIR; ETRAVIRINE; GSK 364735; HISTONE ACETYLTRANSFERASE P300; INDOLE DERIVATIVE; INTEGRASE; INTEGRASE INHIBITOR; LENS EPITHELIUM DERIVED GROWTH FACTOR; MADURAHYDROXYLACTONE DERIVATIVE; N (4 FLUOROBENZYL) 8 HYDROXY 5 (TETRAHYDRO 2H 1,2 THIAZIN 2 YL) 1,6 NAPHTHYRIDINE 7 CARBOXAMIDE S,S DIOXIDE; N (CYCLOHEXYLMETHYL) 2,3 DIHYDROXY 5 (PIPERIDIN 1 YLSULFONYL)BENZAMIDE; N BIS(4 METHOXYPHENYL)METHYLBENZAMIDE; N,N' (METHYLENE DI 4,1 PHENYLENE)BIS 1 PYRROLIDINEACETAMIDE; PEPTIDOMIMETIC AGENT; PROTEIN P75; PROTEIN VPR15; RALTEGRAVIR; RIBONUCLEASE H; RITONAVIR; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANTIVIRAL ACTIVITY; ANTIVIRAL RESISTANCE; CATALYSIS; CLINICAL TRIAL (TOPIC); DNA VIRUS; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG EFFICACY; DRUG MECHANISM; DRUG PROTEIN BINDING; DRUG STRUCTURE; DRUG TARGETING; DRUG TOLERABILITY; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME INHIBITION; GENE MUTATION; GENE THERAPY; GENOME; HOST CELL; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; PROTEIN PROTEIN INTERACTION; REVIEW; STRUCTURE ACTIVITY RELATION; VIRUS DNA CELL DNA INTERACTION; VIRUS INHIBITION; VIRUS LOAD; VIRUS REPLICATION;

ALLOSTERIC REGULATION; ANIMALS; CATALYTIC DOMAIN; DRUG RESISTANCE, VIRAL; ENZYME ACTIVATORS; GENETIC THERAPY; HIV; HIV INFECTIONS; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HUMANS; MODELS, MOLECULAR; PROTEIN CONFORMATION; PROTEIN MULTIMERIZATION; VIRUS INTEGRATION;

EID: 84894026316     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm500961p     Document Type: Erratum

References (283)

1. Gottlieb, M. S.; Schroff, R.; Schanker, H. M; Weisman, J. D.; Fan, P. T; Wolf, R. A.; Saxon, A. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency N. Engl. J. Med. 1981, 305, 1425-1431
2. Masur, H.; Michelis, M. A.; Greene, J. B.; Onorato, I.; Stouwe, R. A.; Holzman, R. S.; Wormser, G.; Brettman, L.; Lange, M.; Murray, H. W.; Cunningham-Rundles, S. An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction N. Engl. J. Med. 1981, 305, 1431-1438
3. Siegal, F. P.; Lopez, C.; Hammer, G. S.; Brown, A. E.; Kornfeld, S. J.; Gold, J.; Hassett, J.; Hirschman, S. Z.; Cunningham-Rundles, C.; Adelsberg, B. R.; Parham, D. M.; Siegal, M.; Cunningham-Rundles, S.; Armstrong, D. Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions N. Engl. J. Med. 1981, 305, 1439-1444
4. Barton, K. M.; Burch, B. D.; Soriano-Sarabia, N.; Margolis, D. M. Prospects for treatment of latent HIV Clin. Pharmacol. Ther. 2013, 93, 46-56
5. Cohen, J. Therapies. Confronting the limits of success Science 2002, 296, 2320-2324
6. Meadows, D. C.; Gervay-Hague, J. Current developments in HIV chemotherapy ChemMedChem 2006, 1, 16-29
7. De Clercq, E. New approaches toward anti-HIV chemotherapy J. Med. Chem. 2005, 48, 1297-1313
8. Yin, P.; Das, D.; Mitsuya, H. Overcoming HIV drug resistance through rational drug design based on molecular, biochemical, and structural profiles of HIV resistance Cell. Mol. Life Sci. 2006, 63, 1706-1724
9. Imamichi, T. Action of anti-HIV drugs and resistance: reverse transcriptase inhibitors and protease inhibitors Curr. Pharm. Des. 2004, 10, 4039-4053
10. Meanwell, N. A.; Kadow, J. F. Maraviroc, a chemokine CCR5 receptor antagonist for the treatment of HIV infection and AIDS Curr. Opin. Invest. Drugs 2007, 8, 669-681
11. Dayam, R.; Gundla, R.; Al-Mawsawi, L. Q.; Neamati, N. HIV-1 integrase inhibitors: 2005-2006 update Med. Res. Rev. 2008, 28, 118-154
12. Evering, T. H.; Markowitz, M. Raltegravir (MK-0518): an integrase inhibitor for the treatment of HIV-1 Drugs Today 2007, 43, 865-877
13. Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi, M.; Ferrara, M.; Fiore, F.; Gardelli, C.; Paz, O. G.; Hazuda, D. J.; Jones, P.; Kinzel, O.; Laufer, R.; Monteagudo, E.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli, R.; Stillmock, K.; Witmer, M. V.; Rowley, M. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection J. Med. Chem. 2008, 51, 5843-5855
14. Shimura, K.; Kodama, E.; Sakagami, Y.; Matsuzaki, Y.; Watanabe, W.; Yamataka, K.; Watanabe, Y.; Ohata, Y.; Doi, S.; Sato, M.; Kano, M.; Ikeda, S.; Matsuoka, M. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137) J. Virol. 2008, 82, 764-774
15. Sato, M.; Motomura, T.; Aramaki, H.; Matsuda, T.; Yamashita, M.; Ito, Y.; Kawakami, H.; Matsuzaki, Y.; Watanabe, W.; Yamataka, K.; Ikeda, S.; Kodama, E.; Matsuoka, M.; Shinkai, H. Novel HIV-1 integrase inhibitors derived from quinolone antibiotics J. Med. Chem. 2006, 49, 1506-1508
16. Sato, M.; Kawakami, H.; Motomura, T.; Aramaki, H.; Matsuda, T.; Yamashita, M.; Ito, Y.; Matsuzaki, Y.; Yamataka, K.; Ikeda, S.; Shinkai, H. Quinolone carboxylic acids as a novel monoketo acid class of human immunodeficiency virus type 1 integrase inhibitors J. Med. Chem. 2009, 52, 4869-4882
17. Katlama, C.; Murphy, R. Dolutegravir for the treatment of HIV Expert Opin. Invest. Drugs 2012, 21, 523-530
18. Zhu, K.; Dobard, C.; Chow, S. A. Requirement for integrase during reverse transcription of human immunodeficiency virus type 1 and the effect of cysteine mutations of integrase on its interactions with reverse transcriptase J. Virol. 2004, 78, 5045-5055
19. Engelman, A.; Englund, G.; Orenstein, J. M.; Martin, M. A.; Craigie, R. Multiple effects of mutations in human immunodeficiency virus type 1 integrase on viral replication J. Virol. 1995, 69, 2729-2736
20. Ellison, V.; Abrams, H.; Roe, T.; Lifson, J.; Brown, P. Human immunodeficiency virus integration in a cell-free system J. Virol. 1990, 64, 2711-2715
21. Bushman, F. D.; Fujiwara, T.; Craigie, R. Retroviral DNA integration directed by HIV integration protein in vitro Science 1990, 249, 1555-1558
22. Craigie, R.; Mizuuchi, K.; Bushman, F. D.; Engelman, A. A rapid in vitro assay for HIV DNA integration Nucleic Acids Res. 1991, 19, 2729-2734
23. Miller, M. D.; Farnet, C. M.; Bushman, F. D. Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition J. Virol. 1997, 71, 5382-5390
24. Farnet, C. M.; Haseltine, W. A. Determination of viral proteins present in the human immunodeficiency virus type 1 preintegration complex J. Virol. 1991, 65, 1910-1915
25. Bukrinsky, M. I.; Sharova, N.; McDonald, T. L.; Pushkarskaya, T.; Tarpley, W. G.; Stevenson, M. Association of integrase, matrix, and reverse transcriptase antigens of human immunodeficiency virus type 1 with viral nucleic acids following acute infection Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 6125-6129
26. Heinzinger, N. K.; Bukrinsky, M. I.; Haggerty, S. A.; Ragland, A. M.; Kewalramani, V.; Lee, M.; Gendelman, H. E.; Ratner, L.; Stevenson, M.; Emerman, M. The vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 7311-7315
27. Buckman, J. S.; Bosche, W. J.; Gorelick, R. J. Human immunodeficiency virus type 1 nucleocapsid Zn(2+) fingers are required for efficient reverse transcription, initial integration processes, and protection of newly synthesized viral DNA J. Virol. 2003, 77, 1469-1480
28. Lapadat-Tapolsky, M.; De Rocquigny, H.; Van Gent, D.; Roques, B.; Plasterk, R.; Darlix, J. L. Interactions between HIV-1 nucleocapsid protein and viral DNA may have important functions in the viral life cycle Nucleic Acids Res. 1993, 21, 831-839
29. Yamashita, M.; Emerman, M. The cell cycle independence of HIV infections is not determined by known karyophilic viral elements PLoS Pathog. 2005, 1, e18
30. Rivière, L.; Darlix, J.-L.; Cimarelli, A. Analysis of the viral elements required in the nuclear import of HIV-1 DNA J. Virol. 2010, 84, 729-739
31. Turlure, F.; Devroe, E.; Silver, P.; Engelman, A. Human cell proteins and human immunodeficiency virus DNA integration Front. Biosci. 2004, 9, 3187-3208
32. Schweitzer, C. J.; Jagadish, T.; Haverland, N.; Ciborowski, P.; Belshan, M. Proteomic analysis of early HIV-1 nucleoprotein complexes J. Proteome Res. 2013, 12, 559-572
33. Cai, M.; Huang, Y.; Caffrey, M.; Zheng, R.; Craigie, R.; Clore, G. M.; Gronenborn, A. M. Solution structure of the His12→Cys mutant of the N-terminal zinc binding domain of HIV-1 integrase complexed to cadmium Protein Sci. 1998, 7, 2669-2674
34. Goldgur, Y.; Dyda, F.; Hickman, A. B.; Jenkins, T. M.; Craigie, R.; Davies, D. R. Three new structures of the core domain of HIV-1 integrase: an active site that binds magnesium Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 9150-9154
35. Lodi, P. J.; Ernst, J. A.; Kuszewski, J.; Hickman, A. B.; Engelman, A.; Craigie, R.; Clore, G. M.; Gronenborn, A. M. Solution structure of the DNA binding domain of HIV-1 integrase Biochemistry 1995, 34, 9826-9833
36. Goldgur, Y.; Craigie, R.; Cohen, G. H.; Fujiwara, T.; Yoshinaga, T.; Fujishita, T.; Sugimoto, H.; Endo, T.; Murai, H.; Davies, D. R. Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: a platform for antiviral drug design Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 13040-13043
37. Wang, J. Y.; Ling, H.; Yang, W.; Craigie, R. Structure of a two-domain fragment of HIV-1 integrase: implications for domain organization in the intact protein EMBO J. 2001, 20, 7333-7343
38. Chen, J. C.; Krucinski, J.; Miercke, L. J.; Finer-Moore, J. S.; Tang, A. H.; Leavitt, A. D.; Stroud, R. M. Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: a model for viral DNA binding Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 8233-8238
39. McKee, C. J.; Kessl, J. J.; Shkriabai, N.; Dar, M. J.; Engelman, A.; Kvaratskhelia, M. Dynamic modulation of HIV-1 integrase structure and function by cellular LEDGF protein J. Biol. Chem. 2008, 283, 31802-31812
40. Sluis-Cremer, N.; Tachedjian, G. Modulation of the oligomeric structures of HIV-1 retroviral enzymes by synthetic peptides and small molecules Eur. J. Biochem. 2002, 269, 5103-5111
41. Karki, R. G.; Tang, Y.; Burke, T. R., Jr.; Nicklaus, M. C. Model of full-length HIV-1 integrase complexed with viral DNA as template for anti-HIV drug design J. Comput.-Aided Mol. Des. 2004, 18, 739-760
42. Hare, S.; Gupta, S. S.; Valkov, E.; Engelman, A.; Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer Nature 2010, 464, 232-236
43. Krishnan, L.; Li, X.; Naraharisetty, H. L.; Hare, S.; Cherepanov, P.; Engelman, A. Structure-based modeling of the functional HIV-1 intasome and its inhibition Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 15910-15915
44. Cherepanov, P.; Ambrosio, A. L.; Rahman, S.; Ellenberger, T.; Engelman, A. Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75 Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 17308-17313
45. Dyda, F.; Hickman, A. B.; Jenkins, T. M.; Engelman, A.; Craigie, R.; Davies, D. R. Crystal structure of the catalytic domain of HIV-1 integrase: similarity to other polynucleotidyl transferases Science 1994, 266, 1981-1986
46. Rice, P. A.; Baker, T. A. Comparative architecture of transposase and integrase complexes Nat. Struct. Biol. 2001, 8, 302-307
47. Beese, L. S.; Steitz, T. A. Structural basis for the 3′-5′ exonuclease activity of Escherichia coli DNA polymerase I: a two metal ion mechanism EMBO J. 1991, 10, 25-33
48. Steitz, T. A.; Steitz, J. A. A general two-metal-ion mechanism for catalytic RNA Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 6498-6502
49. Steitz, T. A. DNA polymerases: structural diversity and common mechanisms J. Biol. Chem. 1999, 274, 17395-17398
50. Steitz, T. A. A mechanism for all polymerases Nature 1998, 391, 231-232
51. Horton, N. C.; Perona, J. J. Making the most of metal ions Nat. Struct. Biol. 2001, 8, 290-293
52. Engelman, A.; Mizuuchi, K.; Craigie, R. HIV-1 DNA integration: mechanism of viral DNA cleavage and DNA strand transfer Cell 1991, 67, 1211-1221
53. Gerton, J. L.; Herschlag, D.; Brown, P. O. Stereospecificity of reactions catalyzed by HIV-1 integrase J. Biol. Chem. 1999, 274, 33480-33487
54. Mazumder, A.; Neamati, N.; Pilon, A. A.; Sunder, S.; Pommier, Y. Chemical trapping of ternary complexes of human immunodeficiency virus type 1 integrase, divalent metal, and DNA substrates containing an abasic site. Implications for the role of lysine 136 in DNA binding J. Biol. Chem. 1996, 271, 27330-27338
55. Marchand, C.; Johnson, A. A.; Karki, R. G.; Pais, G. C.; Zhang, X.; Cowansage, K.; Patel, T. A.; Nicklaus, M. C.; Burke, T. R., Jr.; Pommier, Y. Metal-dependent inhibition of HIV-1 integrase by beta-diketo acids and resistance of the soluble double-mutant (F185K/C280S) Mol. Pharmacol. 2003, 64, 600-609
56. Marchand, C.; Neamati, N.; Pommier, Y. In vitro human immunodeficiency virus type 1 integrase assays Methods Enzymol. 2001, 340, 624-633
57. Craigie, R. HIV integrase, a brief overview from chemistry to therapeutics J. Biol. Chem. 2001, 276, 23213-23216
58. Pemberton, I. K.; Buckle, M.; Buc, H. The metal ion-induced cooperative binding of HIV-1 integrase to DNA exhibits a marked preference for Mn(II) rather than Mg(II) J. Biol. Chem. 1996, 271, 1498-1506
59. Nowotny, M.; Yang, W. Stepwise analyses of metal ions in RNase H catalysis from substrate destabilization to product release EMBO J. 2006, 25, 1924-1933
60. 2+ -ion catalysis and substrate specificity Mol. Cell 2006, 22, 5-13
61. Craigie, R. HIV integrase, a brief overview from chemistry to therapeutics J. Biol. Chem. 2001, 276, 23213-23216
62. Hare, S.; Maertens, G. N.; Cherepanov, P. 3′-Processing and strand transfer catalysed by retroviral integrase in crystallo EMBO J. 2012, 31, 3020-3028
63. Yoder, K. E.; Bushman, F. D. Repair of gaps in retroviral DNA integration intermediates J. Virol. 2000, 74, 11191-11200
64. Daniel, R.; Greger, J. G.; Katz, R. A.; Taganov, K. D.; Wu, X.; Kappes, J. C.; Skalka, A. M. Evidence that stable retroviral transduction and cell survival following DNA integration depend on components of the nonhomologous end joining repair pathway J. Virol. 2004, 78, 8573-8581
65. Carteau, S.; Hoffmann, C.; Bushman, F. Chromosome structure and human immunodeficiency virus type 1 cDNA integration: centromeric alphoid repeats are a disfavored target J. Virol. 1998, 72, 4005-4014
66. Schröder, A. R.; Shinn, P.; Chen, H.; Berry, C.; Ecker, J. R.; Bushman, F. HIV-1 integration in the human genome favors active genes and local hotspots Cell 2002, 110, 521-529
67. Maurin, C.; Bailly, F.; Cotelle, P. Structure-activity relationships of HIV-1 integrase inhibitors-enzyme-ligand interactions Curr. Med. Chem. 2003, 10, 1795-1810
68. Singh, S. B.; Jayasuriya, H.; Salituro, G. M.; Zink, D. L.; Shafiee, A.; Heimbuch, B.; Silverman, K. C.; Lingham, R. B.; Genilloud, O.; Teran, A.; Vilella, D.; Felock, P.; Hazuda, D. The complestatins as HIV-1 integrase inhibitors. Efficient isolation, structure elucidation, and inhibitory activities of isocomplestatin, chloropeptin I, new complestatins, A and B, and acid-hydrolysis products of chloropeptin I J. Nat. Prod. 2001, 64, 874-882
69. Jing, N.; Xu, X. Rational drug design of DNA oligonucleotides as HIV inhibitors Curr. Drug Targets: Infect. Disord. 2001, 1, 79-90
70. Fesen, M. R.; Kohn, K. W.; Leteurtre, F.; Pommier, Y. Inhibitors of human immunodeficiency virus integrase Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 2399-2403
71. Mazumder, A.; Gazit, A.; Levitzki, A.; Nicklaus, M.; Yung, J.; Kohlhagen, G.; Pommier, Y. Effects of tyrphostins, protein kinase inhibitors, on human immunodeficiency virus type 1 integrase Biochemistry 1995, 34, 15111-15122
72. Fesen, M. R.; Pommier, Y.; Leteurtre, F.; Hiroguchi, S.; Yung, J.; Kohn, K. W. Inhibition of HIV-1 integrase by flavones, caffeic acid phenethyl ester (CAPE) and related compounds Biochem. Pharmacol. 1994, 48, 595-608
73. Lin, Z.; Neamati, N.; Zhao, H.; Kiryu, Y.; Turpin, J. A.; Aberham, C.; Strebel, K.; Kohn, K.; Witvrouw, M.; Pannecouque, C.; Debyser, Z.; De Clercq, E.; Rice, W. G.; Pommier, Y.; Burke, T. R., Jr. Chicoric acid analogues as HIV-1 integrase inhibitors J. Med. Chem. 1999, 42, 1401-1414
74. Artico, M.; Di Santo, R.; Costi, R.; Novellino, E.; Greco, G.; Massa, S.; Tramontano, E.; Marongiu, M. E.; De Montis, A.; La Colla, P. Geometrically and conformationally restrained cinnamoyl-compounds as inhibitors of HIV-1 integrase: synthesis, biological evaluation and molecular modeling J. Med. Chem. 1998, 41, 3948-3960
75. Di Santo, R.; Costi, R.; Artico, M.; Tramontano, E.; La Colla, P.; Pani, A. HIV-1 integrase inhibitors that block HIV-1 replication in infected cells. Planning synthetic derivatives from natural products Pure Appl. Chem. 2003, 75, 195-206
76. Costi, R.; Di Santo, R.; Artico, M.; Massa, S.; Ragno, R.; Loddo, R.; La Colla, M.; Tramomtano, E.; La Colla, P.; Pani, A. 2,6-Bis(3,4,5- trihydroxybenzylidene) derivatives of cyclohexanone: novel potent HIV-1 integrase inhibitors that prevent HIV-1 multiplication in cell-based assays Bioorg. Med. Chem. 2004, 12, 199-215
77. Pluymers, W.; Neamati, N.; Pannecouque, C.; Fikkert, V.; Marchand, C.; Burke, T. R., Jr.; Pommier, Y.; Schols, D.; De Clercq, E.; Debyser, Z.; Witvrouw, M. Viral entry as the primary target for the anti-HIV activity of chicoric acid and its tetra-acetyl esters Mol. Pharmacol. 2000, 58, 641-648
78. Hazuda, D. J.; Felock, P.; Witmer, M.; Wolfe, A.; Stillmock, K.; Grobler, J. A.; Espeseth, A.; Gabryelski, L.; Schleif, W.; Blau, C.; Miller, M. D. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells Science 2000, 287, 646-650
79. Fujishita, T.; Yoshinaga, T.; Sato, A. Aromatic Heterocycle Compounds Having HIV Integrase Inhibiting Activities. WO2000039086, June 6, 2000.
80. Fikkert, V.; Van Maele, B.; Vercammen, J.; Hantson, A.; Van Remoortel, B.; Michiels, M.; Gurnari, C.; Pannecouque, C.; De Maeyer, M.; Engelborghs, Y.; De Clercq, E.; Debyser, Z.; Witvrouw, M. Development of resistance against diketo derivatives of human immunodeficiency virus type 1 by progressive accumulation of integrase mutations J. Virol. 2003, 77, 11459-11470
81. Karki, R. G.; Pais, G. C.; Zhang, X.; Cowansage, K.; Patel, T. A.; Nicklaus, M. C.; Burke, T. R., Jr.; Pommier, Y. Metal-dependent inhibition of HIV-1 integrase by {beta}-diketo acids and resistance of the soluble double-mutant (F185K/C280S) Mol. Pharmacol. 2003, 64, 600-609
82. Johnson, A. A.; Marchand, C.; Patil, S. S.; Costi, R.; Di Santo, R.; Burke, T. R., Jr.; Pommier, Y. Probing HIV-1 integrase inhibitor binding sites with position-specific integrase-DNA cross-linking assays Mol. Pharmacol. 2007, 71, 893-901
83. Espeseth, A. S.; Felock, P.; Wolfe, A.; Witmer, M.; Grobler, J.; Anthony, N.; Egbertson, M.; Melamed, J. Y.; Young, S.; Hamill, T.; Cole, J. L.; Hazuda, D. J. HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 11244-11249
84. Marchand, C.; Zhang, X.; Pais, G. C.; Cowansage, K.; Neamati, N.; Burke, T. R., Jr.; Pommier, Y. Structural determinants for HIV-1 integrase inhibition by beta-diketo acids J. Biol. Chem. 2002, 277, 12596-12603
85. Pais, G. C.; Zhang, X.; Marchand, C.; Neamati, N.; Cowansage, K.; Svarovskaia, E. S.; Pathak, V. K.; Tang, Y.; Nicklaus, M. C.; Pommier, Y.; Burke, T. R., Jr. Structure activity of 3-aryl-1,3-diketo-containing compounds as HIV-1 integrase inhibitors J. Med. Chem. 2002, 45, 3184-3194
86. Grobler, J. A.; Stillmock, K. A.; Hazuda, D. J. Scintillation proximity assays for mechanistic and pharmacological analyses of HIV-1 integration Methods 2009, 47, 249-253
87. Costi, R.; Di Santo, R.; Artico, M.; Roux, A.; Ragno, R.; Massa, S.; Tramontano, E.; La Colla, M.; Loddo, R.; Marongiu, M. E.; Pani, A.; La Colla, P. 6-Aryl-2,4-dioxo-5-hexenoic acids, novel integrase inhibitors active against HIV-1 multiplication in cell-based assays Bioorg. Med. Chem. Lett. 2004, 14, 1745-1749
88. Di Santo, R.; Costi, R.; Artico, M.; Roux, A.; Ragno, R.; Greco, G.; Novellino, E.; Marchand, C.; Pommier, Y. Design, synthesis and biological evaluation of heteroaryl diketohexenoic and diketobutanoic acids as HIV-1 integrase inhibitors endowed with antiretroviral activity Farmaco 2005, 60, 409-417
89. Di Santo, R.; Costi, R.; Roux, A.; Artico, M.; Lavecchia, A.; Marinelli, L.; Novellino, E.; Palmisano, L.; Andreotti, M.; Amici, R.; Galluzzo, C. M.; Nencioni, L.; Palamara, A. T.; Pommier, Y.; Marchand, C. Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors: design, synthesis, biological activities and mechanism of action J. Med. Chem. 2006, 49, 1939-1945
90. Di Santo, R.; Costi, R.; Roux, A.; Miele, G.; Cuzzucoli Crucitti, G.; Iacovo, A.; Rosi, F.; Lavecchia, A.; Marinelli, L.; Di Giovanni, C.; Novellino, E.; Palmisano, L.; Andreotti, M.; Amici, R.; Galluzzo, C. M.; Nencioni, L.; Palamara, A. T.; Pommier, Y.; Marchand, C. Novel quinolinonyl diketo acid derivatives as HIV-1 integrase inhibitors: design, synthesis and biological activities J. Med. Chem. 2008, 51, 4744-4750
91. Zhuang, L.; Wai, J. S.; Embrey, M. W.; Fisher, T. E.; Egbertson, M. S.; Payne, L. S.; Guare, J. P., Jr.; Vacca, J. P.; Hazuda, D. J.; Felock, P. J.; Wolfe, A. L.; Stillmock, K. A.; Witmer, M. V.; Moyer, G.; Schleif, W. A.; Gabryelski, L. J.; Leonard, Y. M.; Lynch, J. J., Jr.; Michelson, S. R.; Young, S. D. Design and synthesis of 8-hydroxy-[1,6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells J. Med. Chem. 2003, 46, 453-456
92. Guare, J. P.; Wai, J. S.; Gomez, R. P.; Anthony, N. J.; Jolly, S. M.; Cortes, A. R.; Vacca, J. P.; Felock, P. J.; Stillmock, K. A.; Schleif, W. A.; Moyer, G.; Gabryelski, L. J.; Jin, L.; Chen, I. W.; Hazuda, D. J.; Young, S. D. A series of 5-aminosubstituted 4-fluorobenzyl-8-hydroxy-[1,6]naphthyridine-7- carboxamide HIV-1 integrase inhibitors Bioorg. Med. Chem. Lett. 2006, 16, 2900-2904
93. Hazuda, D. J.; Young, S. D.; Guare, J. P.; Anthony, N. J.; Gomez, R. P.; Wai, J. S.; Vacca, J. P.; Handt, L.; Motzel, S. L.; Klein, H. G.; Dornadula, G.; Danovich, R. M.; Witmer, M. V.; Wilson, K. A.; Tussey, L.; Schleif, W. A.; Gabryelski, L. S.; Jin, L.; Miller, M. D.; Casimiro, D. R.; Emini, E. A.; Shiver, J. W. Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques Science 2004, 305, 528-532
94. Hazuda, D. J.; Anthony, N. J.; Gomez, R. P.; Jolly, S. M.; Wai, J. S.; Zhuang, L.; Fisher, T. E.; Embrey, M.; Guare, J. P., Jr.; Egbertson, M. S.; Vacca, J. P.; Huff, J. R.; Felock, P. J.; Witmer, M. V.; Stillmock, K. A.; Danovich, R.; Grobler, J.; Miller, M. D.; Espeseth, A. S.; Jin, L.; Chen, I. W.; Lin, J. H.; Kassahun, K.; Ellis, J. D.; Wong, B. K.; Xu, W.; Pearson, P. G.; Schleif, W. A.; Cortese, R.; Emini, E.; Summa, V.; Holloway, M. K.; Young, S. D. A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11233-11238
95. Garvey, E. P.; Johns, B. A.; Gartland, M. J.; Foster, S. A.; Miller, W. H.; Ferris, R. G.; Hazen, R. J.; Underwood, M. R.; Boros, E. E.; Thompson, J. B.; Weatherhead, J. G.; Koble, C. S.; Allen, S. H.; Schaller, L. T.; Sherrill, R. G.; Yoshinaga, T.; Kobayashi, M.; Wakasa-Morimoto, C.; Miki, S.; Nakahara, K.; Noshi, T.; Sato, A.; Fujiwara, T. The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral Antimicrob. Agents Chemother. 2008, 52, 901-908
96. Johns, B. A.; Weatherhead, J. G.; Allen, S. H.; Thompson, J. B.; Garvey, E. P.; Foster, S. A.; Jeffrey, J. L.; Miller, W. H. The use of oxadiazole and triazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 1: establishing the pharmacophore Bioorg. Med. Chem. Lett. 2009, 19, 1802-1806
97. Johns, B. A.; Weatherhead, J. G.; Allen, S. H.; Thompson, J. B.; Garvey, E. P.; Foster, S. A.; Jeffrey, J. L.; Miller, W. H. 1,3,4-Oxadiazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 2: SAR of the C5 position Bioorg. Med. Chem. Lett. 2009, 19, 1807-1810
98. Metobo, S. E.; Jin, H.; Tsiang, M.; Kim, C. U. Design, synthesis, and biological evaluation of novel tricyclic HIV-1 integrase inhibitors by modification of its pyridine ring Bioorg. Med. Chem. Lett. 2006, 16, 3985-3988
99. Jones, G. S.; Yu, F.; Zeynalzadegan, A.; Hesselgesser, J.; Chen, X.; Chen, J.; Jin, H.; Kim, C. U.; Wright, M.; Geleziunas, R.; Tsiang, M. Preclinical evaluation of GS-9160, a novel inhibitor of human immunodeficiency virus type 1 integrase Antimicrob. Agents Chemother. 2009, 53, 1194-1203
100. Pandey, K. K.; Bera, S.; Zahm, J.; Vora, A.; Stillmock, K.; Hazuda, D.; Grandgenett, D. P. Inhibition of human immunodeficiency virus type 1 concerted integration by strand transfer inhibitors which recognize a transient structural intermediate J. Virol. 2007, 81, 12189-12199
101. Petrocchi, A.; Koch, U.; Matassa, V. G.; Pacini, B.; Stillmock, K. A.; Summa, V. From dihydroxypyrimidine carboxylic acids to carboxamide HIV-1 integrase inhibitors: SAR around the amide moiety Bioorg. Med. Chem. Lett. 2007, 17, 350-353
102. Summa, V.; Petrocchi, A.; Matassa, V. G.; Gardelli, C.; Muraglia, E.; Rowley, M.; Paz, O. G.; Laufer, R.; Monteagudo, E.; Pace, P. 4,5-Dihydroxypyrimidine carboxamides and N -alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic profiles in preclinical species J. Med. Chem. 2006, 49, 6646-6649
103. Anker, M.; Corales, R. B. Raltegravir (MK-0518): a novel integrase inhibitor for the treatment of HIV infection Expert Opin. Invest. Drugs 2008, 17, 97-103
104. Grinsztejn, B.; Nguyen, B. Y.; Katlama, C.; Gatell, J. M.; Lazzarin, A.; Vittecoq, D.; Gonzalez, C. J.; Chen, J.; Harvey, C. M.; Isaacs, R. D. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial Lancet 2007, 369, 1261-1269
105. Lennox, J. L.; DeJesus, E.; Lazzarin, A.; Pollard, R. B.; Madruga, J. V.; Berger, D. S.; Zhao, J.; Xu, X.; Williams-Diaz, A.; Rodgers, A. J.; Barnard, R. J.; Miller, M. D.; DiNubile, M. J.; Nguyen, B. Y.; Leavitt, R.; Sklar, P. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial Lancet 2009, 374, 796-806
106. Markowitz, M.; Nguyen, B. Y.; Gotuzzo, E.; Mendo, F.; Ratanasuwan, W.; Kovacs, C.; Prada, G.; Morales-Ramirez, J. O.; Crumpacker, C. S.; Isaacs, R. D.; Gilde, L. R.; Wan, H.; Miller, M. D.; Wenning, L. A.; Teppler, H. Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study J. Acquired Immune Defic. Syndr. 2007, 46, 125-133
107. Steigbigel, R. T.; Cooper, D. A.; Kumar, P. N.; Eron, J. E.; Schechter, M.; Markowitz, M.; Loutfy, M. R.; Lennox, J. L.; Gatell, J. M.; Rockstroh, J. K.; Katlama, C.; Yeni, P.; Lazzarin, A.; Clotet, B.; Zhao, J.; Chen, J.; Ryan, D. M.; Rhodes, R. R.; Killar, J. A.; Gilde, L. R.; Strohmaier, K. M.; Meibohm, A. R.; Miller, M. D.; Hazuda, D. J.; Nessly, M. L.; DiNubile, M. J.; Isaacs, R. D.; Nguyen, B. Y.; Teppler, H. Raltegravir with optimized background therapy for resistant HIV-1 infection N. Eng. J. Med. 2008, 359, 339-354
108. Yazdanpanah, Y.; Fagard, C.; Descamps, D.; Taburet, A. M.; Colin, C.; Roquebert, B.; Katlama, C.; Pialoux, G.; Jacomet, C.; Piketty, C.; Bollens, D.; Molina, J. M.; Cheîne, G. High rate of virologic suppression with raltegravir plus etravirine and darunavir/ritonavir among treatment-experienced patients infected with multidrug-resistant HIV: results of the ANRS 139 TRIO trial Clin. Infect. Dis. 2009, 49, 1441-1449
109. Thuret, I.; Chaix, M. L.; Tamalet, C.; Reliquet, V.; Firtion, G.; Tricoire, J.; Rabaud, C.; Frange, P.; Aumaitre, H.; Blanche, S. Raltegravir, etravirine and darunavir combination in adolescents with multidrug-resistant virus AIDS 2009, 23, 2364-2366
110. McKinnell, J. A.; Lin, H. Y.; Nevin, C. N.; Willig, J. H.; McFarland, G.; Genz, M.; Raper, J. L.; DeLaitsch, L. L.; Mrus, J. M.; Klaskala, W.; Mugavero, M. J.; Saag, M. S. Early virologic suppression with three-class experienced patients: 24-week effectiveness in the darunavir outcomes study AIDS 2009, 23, 1539-1546
111. Imaz, A.; del Saz, S. V.; Ribas, M. A.; Curran, A.; Caballero, E.; Falcó, V.; Crespo, M.; Ocaña, I.; Diaz, M.; de Gopegui, E. R.; Riera, M.; Ribera, E. Raltegravir, etravirine, and ritonavir-boosted darunavir: a safe and successful rescue regimen for multidrug-resistant HIV-1 infection J. Acquired Immune Defic. Syndr. 2009, 52, 382-386
112. Towner, W.; Klein, D.; Kerrigan, H. L.; Follansbee, S.; Yu, K.; Horberg, M. Virologic outcomes of changing enfuvirtide to raltegravir in HIV-1 patients well controlled on an enfuvirtide based regimen: 24-week results of the CHEER study J. Acquired Immune Defic. Syndr. 2009, 51, 367-373
113. De Castro, N.; Braun, J.; Charreau, I.; Pialoux, G.; Cotte, L.; Katlama, C.; Raffi, F.; Weiss, L.; Meynard, J. L.; Yazdanpanah, Y.; Delaugerre, C.; Madelaine-Chambrin, I.; Aboulker, J. P.; Molina, J. M. Switch from enfuvirtide to raltegravir in virologically suppressed multidrug-resistant HIV-1-infected patients: a randomized open-label trial Clin. Infect. Dis. 2009, 49, 1259-1267
114. Grant, P. M.; Palmer, S.; Bendavid, E.; Talbot, A.; Slamowitz, D. C.; Cain, P.; Kobayashi, S. S.; Balamane, M.; Zolopa, A. R. Switch from enfuvirtide to raltegravir in virologically suppressed HIV-1 infected patients: effects on level of residual viremia and quality of life J. Clin. Virol. 2009, 46, 305-308
115. De Clercq, E. A new drug combination therapy for treatment-naive patients with HIV-1 infection, consisting of raltegravir, emtricitabine and tenofovir disoproxil fumarate Expert Opin. Pharmacother. 2009, 10, 2935-2937
116. Buzon, M. J.; Dalmau, J.; Puertas, M. C.; Puig, J.; Clotet, B.; Martinez-Picado, J. The HIV-1 integrase genotype strongly predicts raltegravir susceptibility but not viral fitness of primary virus isolates AIDS 2010, 24, 17-25
117. Grobler, J. A.; Stillmock, K.; Miller, M. D.; Hazuda, D. J. Mechanism by which the HIV integrase activesite mutation N155H confers resistance to raltegravir Antiviral Ther. 2008, 13, A41
118. Malet, I.; Delelis, O.; Valantin, M. A.; Montes, B.; Soulie, C.; Wirden, M.; Tchertanov, L.; Peytavin, G.; Reynes, J.; Mouscadet, J. F.; Katlama, C.; Calvez, V.; Marcelin, A. G. Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro Antimicrob. Agents Chemother. 2008, 52, 1351-1358
119. Garrido, C.; de Mendoza, C.; Soriano, V. Resistance to integrase inhibitors Enferm. Infecc. Microbiol. Clin. 2008, 26, 40-46
120. Bar-Magen, T.; Donahue, D. A.; McDonough, E. I.; Kuhl, B. D.; Faltenbacher, V. H.; Xu, H.; Michaud, V.; Sloan, R. D.; Wainberg, M. A. HIV-1 subtype B and C integrase enzymes exhibit differential patterns of resistance to integrase inhibitors in biochemical assays AIDS 2010, 24, 2171-2179
121. Delelis, O.; Malet, I.; Na, L.; Tchertanov, L.; Calvez, V.; Marcelin, A. G.; Subra, F.; Deprez, E.; Mouscadet, J. F. The G140S mutation in HIV integrases from raltegravir-resistant patients rescues catalytic defect due to the resistance Q148H mutation Nucleic Acids Res. 2009, 37, 1193-1201
122. Johnson, V. A.; Brun-Vézinet, F.; Clotet, B.; Günthard, H. F.; Kuritzkes, D. R.; Pillay, D.; Schapiro, J. M.; Richman, D. D. Update of the drug resistance mutations in HIV-1: December 2010 Top. HIV Med. 2010, 18, 156-163
123. Langley, D. R.; Samanta, H. K.; Lin, Z.; Walker, M. A.; Krystal, M. R.; Dicker, I. B. The terminal (catalytic) adenosine of the HIV LTR controls the kinetics of binding and dissociation of HIV integrase strand transfer inhibitors Biochemistry 2008, 47, 13481-13488
124. Hare, S.; Vos, A. M.; Clayton, R. F.; Thuring, J. W.; Cummings, M. D.; Cherepanov, P. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20057-20062
125. Klibanov, O. M. Elvitegravir, an oral HIV integrase inhibitor, for the potential treatment of HIV infection Curr. Opin. Invest. Drugs 2009, 10, 190-200
126. Goethals, O.; Clayton, R.; Van Ginderen, M.; Vereycken, I.; Wagemans, E.; Geluykens, P.; Dockx, K.; Strijbos, R.; Smits, V.; Vos, A.; Meersseman, G.; Jochmans, D.; Vermeire, K.; Schols, D.; Hallenberger, S.; Hertogs, K. Resistance mutations in human immunodeficiency virus type 1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors J. Virol. 2008, 82, 10366-10374
127. Taiwo, B.; Zheng, L.; Gallien, S.; Matining, R. M.; Kuritzkes, D. R.; Wilson, C. C.; Berzins, B. I.; Acosta, E. P.; Bastow, B.; Kim, P. S.; Eron, J. J., Jr. ACTG A5262 team: efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262) AIDS 2011, 25, 2113-2122
128. Métifiot, M.; Vandegraaff, N.; Maddali, K.; Naumova, A.; Zhang, X.; Rhodes, D.; Marchand, C.; Pommier, Y. Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143 AIDS 2011, 25, 1175-1178
129. Shimura, K.; Kodama, E.; Sakagami, Y.; Matsuzaki, Y.; Watanabe, W.; Yamataka, K.; Watanabe, Y.; Ohata, Y.; Doi, S.; Sato, M.; Kano, M.; Ikeda, S.; Matsuoka, M. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137) J. Virol. 2008, 82, 764-774
130. Dicker, I. B.; Terry, B.; Lin, Z.; Li, Z.; Bollini, S.; Samanta, H. K.; Gali, V.; Walker, M. A.; Krystal, M. R. Biochemical analysis of HIV-1 integrase variants resistant to strand transfer inhibitors J. Biol. Chem. 2008, 283, 23599-23609
131. McColl, D. J.; Chen, X. Strand transfer inhibitors of HIV-1 integrase: bringing in a new era of antiretroviral therapy Antiviral Res. 2010, 85, 101-118
132. Kobayashi, M.; Yoshinaga, T.; Seki, T.; Wakasa-Morimoto, C.; Brown, K. W.; Ferris, R.; Foster, S. A.; Hazen, R. J.; Miki, S.; Suyama-Kagitani, A.; Kawauchi-Miki, S.; Taishi, T.; Kawasuji, T.; Johns, B. A.; Underwood, M. R.; Garvey, E. P.; Sato, A.; Fujiwara, T. In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor Antimicrob. Agents Chemother. 2011, 55, 813-821
133. Min, S.; Song, I.; Borland, J.; Chen, S.; Lou, Y.; Fujiwara, T.; Piscitelli, S. C. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers Antimicrob. Agents Chemother. 2010, 54, 254-258
134. Min, S.; Sloan, L.; Dejesus, E.; Hawkins, T.; McCurdy, L.; Song, I.; Stroder, R.; Chen, S.; Underwood, M.; Fujiwara, T.; Piscitelli, S.; Lalezari, J. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults AIDS 2011, 25, 1737-1745
135. Quashie, P. K.; Mesplède, T.; Han, Y. S.; Oliveira, M.; Singhroy, D. N.; Fujiwara, T.; Underwood, M. R.; Wainberg, M. A. Characterization of the R263K mutation in HIV-1 integrase that confers low-level resistance to the second generation integrase strand transfer inhibitor dolutegravir J. Virol. 2012, 86, 2696-2705
136. Eron, J.; Livrozet, J. M.; Morlat, P.; Lazzarin, A.; Katlama, C.; Hawkins, T.; Fujiwara, T.; Cuffe, R.; Vavro, C.; Santiago, J.; Ait-Khaled, M.; Min, S.; Yeo, J. M. Activity of integrase inhibitor S/GSK9572 in subjects with HIV exhibiting raltegravir resistance: week 24 results of VIKING study J. Int. AIDS Soc. 2010, 13 (Suppl. 4) O51
137. Sloan, R. D.; Wainberg, M. A. The role of unintegrated DNA in HIV infection Retrovirology 2011, 8, 52
138. Underwood, M.; Johns, B.; Sato, A.; Fujiwara, T.; Spreen, W. S/GSK1349572: A Next Generation Integrase Inhibitor with Activity against Integrase Inhibitor-Resistant Clinical Isolates from Patients Experiencing Virologic Failure while on Raltegravir Therapy. Presented at the 5th International AIDS Society's Conference on HIV Pathogenesis, Cape Town, South Africa, 2009. Levin, J. Conference Reports for NATAP, 2009; http://www.natap. org/2009/IAS/IAS-06.htm.
139. Wiscount, C. M.; Williams, P. D.; Tran, L. O.; Embrey, M. W.; Fisher, T. E.; Sherman, V.; Homnick, C. F.; Donnette Staas, D.; Lyle, T. A.; Wai, J. S.; Vacca, J. P.; Wang, Z.; Felock, P. J.; Stillmock, K. A.; Witmer, M. V.; Miller, M. D.; Hazuda, D. J.; Day, A. M.; Gabryelski, L. J.; Ecto, L. T.; Schleif, W. A.; Di Stefano, D. J.; Kochansky, C. J.; Anari, M. R. 10-Hydroxy-7,8- dihydropyrazino[1′,2′:1,5]pyrrolo[2,3- d ]pyridazine-1,9(2 H,6 H)-diones: potent, orally bioavailable HIV-1 integrase strand-transfer inhibitors with activity against integrase mutants Bioorg. Med. Chem. Lett. 2008, 18, 4581-4583
140. Hightower, K. E.; Wang, R.; Deanda, F.; Johns, B. A.; Weaver, K.; Shen, Y.; Tomberlin, G. H.; Carter, H. L.; Broderick, T.; Sigethy, S.; Seki, T.; Kobayashi, M.; Underwood, M. R. Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes Antimicrob. Agents Chemother. 2011, 55, 4552-4559
141. Mascolini, M. Merck offers unique perspective on second-generation integrase inhibitor. http://www.natap.org/2009/PK/PK-10.htm.
142. Hare, S.; Smith, S. J.; Métifiot, M.; Jaxa-Chamiec, A.; Pommier, Y.; Hughes, S. H.; Cherepanov, P. Structural and functional analyses of the second generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572) Mol. Pharmacol. 2011, 80, 565-572
143. Al-Mawsawi, L. Q.; Al-Safi, R. I.; Neamati, N. Anti-infectives: clinical progress of HIV-1 integrase inhibitors Expert Opin. Emerging Drugs 2008, 13, 213-225
144. Van Wesenbeeck, L.; Rondelez, E.; Feyaerts, M.; Verheyen, A.; Van der Borght, K.; Smits, V.; Cleybergh, C.; De Wolf, H.; Van Baelen, K.; Stuyver, L. J. Cross-resistance profile determination of two second-generation HIV-1 integrase inhibitors using a panel of recombinant viruses derived from raltegravir treated clinical isolates Antimicrob. Agents Chemother. 2011, 55, 321-325
145. Pandey, K. K.; Bera, S.; Vora, A. C.; Grandgenett, D. P. Physical trapping of HIV-1 synaptic complex by different structural classes of integrase strand transfer inhibitors Biochemistry 2010, 49, 8376-8387
146. Goethals, O.; van Ginderen, M.; Vos, A.; Cummings, M. D.; van Der Borght, K.; van Wesenbeeck, L.; Feyaerts, M.; Verheyen, A.; Smits, V.; van Loock, M.; Hertogs, K.; Schols, D.; Clayton, R. F. Resistance to raltegravir highlights integrase mutations at codon 148 in conferring cross-resistance to a second generation HIV-1 integrase inhibitor Antiviral Res. 2011, 91, 167-176
147. Bar-Magen, T.; Sloan, R. D.; Donahue, D. A.; Kuhl, B. D.; Zabeida, A.; Xu, H.; Oliveira, M.; Hazuda, D. J.; Wainberg, M. A. Identification of novel mutations responsible for resistance to MK-2048, a second-generation HIV-1 integrase inhibitor J. Virol. 2010, 84, 9210-9216
148. Bar-Magen, T.; Sloan, R. D.; Faltenbacher, V. H.; Donahue, D. A.; Kuhl, B. D.; Oliveira, M.; Xu, H.; Wainberg, M. A. Comparative biochemical analysis of HIV-1 subtype B and C integrase enzymes Retrovirology 2009, 6, 103
149. Delelis, O.; Carayon, K.; Saib, A.; Deprez, E.; Mouscadet, J. F. Integrase and integration: biochemical activities of HIV-1 integrase Retrovirology 2008, 5, 114
150. Highleyman, L. Early studies demonstrate potent activity and safety of experimental integrase inhibitor S/GSK1265744. http://www.hivandhepatitis.com/ 2009icr/icaac/docs/092209-a.html.
151. van Lunzen, J.; Maggiolo, F.; Arribas, J. R.; Rakhmanova, A.; Yeni, P.; Young, B.; Rockstroh, J. K.; Almond, S.; Song, I.; Brothers, C.; Min, S. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial Lancet Infect. Dis. 2012, 12, 111-118
152. Enron, J.; Kumar, P.; Lazzarin, A.; Richmond, G.; Soriano, V.; Huang, J.; Vavro, C.; Ait-Khaled, M.; Min, S.; Yeo, J. DTG in Subjects with HIV Exhibiting RAL Resistance: Functional Monotherapy Results of VIKING Study Cohort II. Presented at the 18th CROI, Conference on Retroviruses and Opportunistic Infections, Boston, MA, 2011; Abstract 151LB.
153. Kobayashi, M.; Seki, T.; Yoshinaga, T.; Sato, A.; Fujiwara, T.; Underwood, M.; Johns, B. Antiviral Activity in Vitro of the INI, Dolutegravir, against Raltegravir-Resistant HIV-2 Mutants. Presented at the 19th CROI, Conference on Retroviruses and Opportunistic Infections, Seattle, WA, 2012; Abstract 691.
154. Mouscadet, J. F.; Delelis, O.; Marcelin, A. G.; Tchertanov, L. Resistance to HIV-1 integrase inhibitors: a structural perspective Drug Resist. Updates 2010, 13, 139-150
155. Blanco, J. L.; Varghese, V.; Rhee, S. Y.; Gatell, J. M.; Shafer, R. W. HIV-1 integrase inhibitor resistance and its clinical implications J. Infect. Dis. 2011, 203, 1204-1214
156. Copeland, R. A.; Pompliano, D. L.; Meek, T. D. Drug-target residence time and its implications for lead optimization Nat. Rev. Drug Discovery 2006, 5, 730-739
157. Mehellou, Y.; De Clercq, E. Twenty-six years of anti-HIV drug discovery: Where do we stand and where do we go? J. Med. Chem. 2010, 53, 521-538
158. Patyar, S.; Prakash, A.; Medhi, B. Dual inhibition: a novel promising pharmacological approach for different disease conditions J. Pharm. Pharmacol. 2011, 63, 459-471
159. Apsel, B.; Blair, J. A.; Gonzalez, B. Z.; Nazif, T. M.; Feldman, M. E.; Aizenstein, B.; Hoffman, R.; Williams, R. L.; Shokat, K. M.; Knight, Z. A. Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases Nat. Chem. Biol. 2008, 4, 691-699
160. Muregi, F. W.; Kirira, P. G.; Ishih, A. Novel rational drug design strategies with potential to revolutionize malaria chemotherapy Curr. Med. Chem. 2011, 18, 113-143
161. Wang, Z.; Bennett, E. M.; Wilson, D. J.; Salomon, C.; Vince, R. Rationally designed dual inhibitors of HIV reverse transcriptase and integrase J. Med. Chem. 2007, 50, 3416-3419
162. Wang, Z.; Vince, R. Synthesis of pyrimidine and quinolone conjugates as a scaffold for dual inhibitors of HIV reverse transcriptase and integrase Bioorg. Med. Chem. Lett. 2008, 18, 1293-1296
163. Wang, Z.; Vince, R. Design and synthesis of dual inhibitors of HIV reverse transcriptase and integrase: introducing a diketoacid functionality into delavirdine Bioorg. Med. Chem. 2008, 16, 3587-3595
164. Kaushik, N.; Rege, N.; Yadav, P. N.; Sarafianos, S. G.; Modak, M. J.; Pandey, V. N. Biochemical analysis of catalytically crucial aspartate mutants of human immunodeficiency virus type 1 reverse transcriptase Biochemistry 1996, 35, 11536-11546
165. Patel, H. P.; Jacobo-Molina, A.; Ding, J.; Tantillo, C.; Clark, A. D.; Raag, R.; Nanni, R. G.; Hughes, S. H.; Arnold, E. Insights into DNA polymerization mechanisms from structure and function analysis of HIV-1 reverse transcriptase Biochemistry 1995, 34, 5351-5363
166. Di Santo, R. Diketo acids derivatives as dual inhibitors of human immunodeficiency virus type 1 integrase and the reverse transcriptase RNase H domain Curr. Med. Chem. 2011, 18, 3335-3342
167. Billamboz, M.; Bailly, F.; Barreca, M. L.; De Luca, L.; Mouscadet, J. F.; Calmels, C.; Andréola, M. L.; Witvrouw, M.; Christ, F.; Debyser, Z.; Cotelle, P. Design, synthesis, and biological evaluation of a series of 2-hydroxyisoquinoline-1,3(2 H,4 H)-diones as dual inhibitors of human immunodeficiency virus type 1 integrase and the reverse transcriptase RNase H domain J. Med. Chem. 2008, 51, 7717-7730
168. Billamboz, M.; Bailly, F.; Lion, C.; Calmels, C.; Andréola, M. L.; Witvrouw, M.; Christ, F.; Debyser, Z.; De Luca, L.; Chimirri, A.; Cotelle, P. 2-Hydroxyisoquinoline-1,3(2 H,4 H)-diones as inhibitors of HIV-1 integrase and reverse transcriptase RNase H domain: influence of the alkylation of position 4 Eur. J. Med. Chem. 2011, 46, 535-546
169. Marchand, C.; Beutler, J. A.; Wamiru, A.; Budihas, S.; Möllmann, U.; Heinisch, L.; Mellors, J. W.; Le Grice, S. F.; Pommier, Y. Madurahydroxylactone derivatives as dual inhibitors of human immunodeficiency virus type 1 integrase and RNase H Antimicrob. Agents Chemother. 2008, 52, 361-364
170. Tramontano, E.; Esposito, F.; Badas, R.; Di Santo, R.; Costi, R.; La Colla, P. 6-[1-(4-Fluorophenyl)methyl-1 H -pyrrol-2-yl)]-2,4-dioxo-5-hexenoic acid ethyl ester a novel diketo acid derivative which selectively inhibits the HIV-1 viral replication in cell culture and the ribonuclease H activity in vitro Antiviral Res. 2005, 65, 117-124
171. Shaw-Reid, C. A.; Munshi, V.; Graham, P.; Wolfe, A.; Witmer, M.; Danzeisen, R.; Olsen, D. B.; Carroll, S. S.; Embrey, M.; Wai, J. S.; Miller, M. D.; Cole, J. L.; Hazuda, D. J. Inhibition of HIV-1 ribonuclease H by a novel diketo acid, 4-[5-(benzoylamino)thien-2-yl]-2,4-dioxobutanoic acid J. Biol. Chem. 2003, 278, 2777-2780
172. Ammar, F. F.; Abdel-Azeim, S.; Zargarian, L.; Hobaika, Z.; Maroun, R. G.; Fermandjian, S. Unprocessed viral DNA could be the primary target of the HIV-1 integrase inhibitor raltegravir PLoS One 2012, 7, e40223
173. Scottoline, B. P.; Chow, S.; Ellison, V.; Brown, P. O. Disruption of the terminal base pairs of retroviral DNA during integration Genes Dev. 1997, 11, 371-382
174. Katz, R. A.; Merkel, G.; Andrake, M. D.; Roder, H.; Skalka, A. M. Retroviral integrases promote fraying of viral DNA ends J. Biol. Chem. 2011, 286, 25710-25718
175. Vink, C.; van Gent, D. C.; Elgersma, Y.; Plasterk, R. H. Human immunodeficiency virus integrase protein requires a subterminal position of its viral DNA recognition sequence for efficient cleavage J. Virol. 1991, 65, 4636-4644
176. Vink, C.; Yeheskiely, E.; van der Marel, G. A.; van Boom, J. H.; Plasterk, R. H. Site-specific hydrolysis and alcoholysis of human immunodeficiency virus DNA termini mediated by the viral integrase protein Nucleic Acids Res. 1991, 19, 6691-6698
177. Agapkina, J.; Smolov, M.; Zubin, E.; Mouscadet, J. F.; Gottikh, M. HIV-1 integrase can process a 39-end crosslinked substrate Eur. J. Biochem. 2004, 271, 205-211
178. Suzuki, Y.; Craigie, R. The road to chromatin-nuclear entry of retroviruses Nat. Rev. Microbiol. 2007, 5, 187-196
179. Turlure, F.; Devroe, E.; Silver, P. A.; Engelman, A. Human cell proteins and human immunodeficiency virus DNA integration Front. Biosci. 2004, 9, 3187-3208
180. Masuda, T. Non-enzymatic functions of retroviral integrase: the next target for novel anti-HIV drug development Front. Microbiol. 2011, 2, 210
181. Fassati, A.; Gorlich, D.; Harrison, I.; Zaytseva, L.; Mingot, J. M. Nuclear import of HIV-1 intracellular reverse transcription complexes is mediated by importin 7 EMBO J. 2003, 22, 3675-3685
182. Ao, Z.; Huang, G.; Yao, H.; Xu, Z.; Labine, M.; Cochrane, A. W.; Yao, X. Interaction of human immunodeficiency virus type 1 integrase with cellular nuclear import receptor importin 7 and its impact on viral replication J. Biol. Chem. 2007, 282, 13456-13467
183. Christ, F.; Thys, W.; De Rijck, J.; Gijsbers, R.; Albanese, A.; Arosio, D.; Emiliani, S.; Rain, J. C.; Benarous, R.; Cereseto, A.; Debyser, Z. Transportin-SR2 imports HIV into the nucleus Curr. Biol. 2008, 18, 1192-1202
184. Woodward, C. L.; Prakobwanakit, S.; Mosessian, S.; Chow, S. A. Integrase interacts with nucleoporin NUP153 to mediate the nuclear import of human immunodeficiency virus type 1 J. Virol. 2009, 83, 6522-6533
185. Van Maele, B.; Busschots, K.; Vandekerckhove, L.; Christ, F.; Debyser, Z. Cellular co-factors of HIV-1 integration Trends Biochem. Sci. 2006, 31, 98-105
186. Hindmarsh, P.; Ridky, T.; Reeves, R.; Andrake, M.; Skalka, A. M.; Leis, J. HMG protein family members stimulate human immunodeficiency virus type 1 and avian sarcoma virus concerted DNA integration in vitro J. Virol. 1999, 73, 2994-3003
187. Farnet, C.; Bushman, F. D. HIV-1 cDNA integration: requirement of HMG I (Y) protein for function of preintegration complexes in vitro Cell 1997, 88, 483-492
188. Kalpana, G. V.; Marmon, S.; Wang, W.; Crabtree, G. R.; Goff, S. P. Binding and stimulation of HIV-1 integrase by a human homolog of yeast transcription factor SNF5 Science 1994, 266, 2002-2006
189. Cherepanov, P.; Maertens, G.; Proost, P.; Devreese, B.; Van Beeumen, J.; Engelborghs, Y.; De Clercq, E.; Debyser, Z. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells J. Biol. Chem. 2002, 278, 372-381
190. Violot, S.; Hong, S. S.; Rakotobe, D.; Petit, C.; Gay, B.; Moreau, K.; Billaud, G.; Priet, S.; Sire, J.; Schwartz, O.; Mouscadet, J. F.; Boulanger, P. The human polycomb group EED protein interacts with the integrase of human immunodeficiency virus type 1 J. Virol. 2003, 77, 12507-12522
191. Al-Mawsawi, L. Q.; Neamati, N. Blocking interactions between HIV-1 integrase and cellular cofactors: an emerging anti-retroviral strategy Trends Pharmacol. Sci. 2007, 28, 526-535
192. Goff, S. P. Host factors exploited by retroviruses Nat. Rev. Microbiol. 2007, 5, 253-263
193. Studamire, B.; Goff, S. P. Interactions of host proteins with the murine leukemia virus integrase Viruses 2010, 2, 1110-1145
194. Yung, E.; Sorin, M.; Wang, E. J.; Perumal, S.; Ott, D.; Kalpana, G. V. Specificity of interaction of INI1/hSNF5 with retroviral integrases and its functional significance J. Virol. 2004, 78, 2222-2231
195. Singh, D. P.; Ohguro, N.; Kikuchi, T.; Sueno, T.; Reddy, V. N.; Yuge, K.; Chylack, L. T., Jr.; Shinohara, T. Lens epithelium-derived growth factor: effects on growth and survival of lens epithelial cells, keratinocytes, and fibroblasts Biochem. Biophys. Res. Commun. 2000, 267, 373-381
196. Engelman, A.; Cherepanov, P. The lentiviral integrase binding protein LEDGF/p75 and HIV-1 replication PLoS Pathog. 2008, 4, e1000046
197. Cherepanov, P.; Maertens, G.; Proost, P.; Devreese, B.; Van Beeumen, J.; Engelborghs, Y.; DeClercq, E.; Debyser, Z. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells J. Biol. Chem. 2003, 278, 372-381
198. Cherepanov, P.; Devroe, E.; Silver, P. A.; Engelman, A. Identification of an evolutionarily conserved domain in human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) that binds HIV-1integrase J. Biol. Chem. 2004, 279, 48883-48892
199. Llano, M.; Saenz, D. T.; Meehan, A.; Wongthida, P.; Peretz, M.; Walker, W. H.; Teo, W.; Poeschla, E. M. An essential role for LEDGF/p75 in HIV integration Science 2006, 314, 461-464
200. Shun, M. C.; Raghavendra, N. K.; Vandegraaff, N.; Daigle, J. E.; Hughes, S.; Kellam, P.; Cherepanov, P.; Engelman, A. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration Genes Dev. 2007, 21, 1767-1778
201. Busschots, K.; Voet, A.; De Maeyer, M.; Rain, J. C.; Emiliani, S.; Benarous, R.; Desender, L.; Debyser, Z.; Christ, F. Identification of the LEDGF/p75 binding site in HIV-1 integrase J. Mol. Biol. 2007, 365, 1480-1492
202. Emiliani, S.; Mousnier, A.; Busschots, K.; Maroun, M.; Van Maele, B.; Tempe, D.; Vandekerckhove, L.; Moisant, F.; Ben-Slama, L.; Witvrouw, M.; Christ, F.; Rain, J. C.; Dargemont, C.; Debyser, Z.; Benarous, R. Integrase mutants defective for interaction with LEDGF/p75 are impaired in chromosome tethering and HIV-1 replication J. Biol. Chem. 2005, 280, 25517-25523
203. Hombrouck, A.; De Rijck, J.; Hendrix, J.; Vandekerckhove, L.; Voet, A.; De Maeyer, M.; Witvrouw, M.; Engelborghs, Y.; Christ, F.; Gijsbers, R.; Debyser, Z. Virus evolution reveals an exclusive role for LEDGF/p75 in chromosomal tethering of HIV PLoS Pathog. 2007, 3, e47
204. Cherepanov, P.; Sun, Z. Y.; Rahman, S.; Maertens, G.; Wagner, G.; Engelman, A. Solution structure of the HIV-1 integrase-binding domain in LEDGF/ p75 Nat. Struct. Mol. Biol. 2005, 12, 526-532
205. Schrijvers, R.; De Rijck, J.; Demeulemeester, J.; Adachi, N.; Vets, S.; Ronen, K.; Christ, F.; Bushman, F. D.; Debyser, Z.; Gijsbers, R. LEDGF/p75-independent HIV- 1 replication demonstrates a role for HRP-2 and remains sensitive to inhibition by LEDGINs PLoS Pathog. 2012, 8, e1002558
206. Vandekerckhove, L.; Christ, F.; Van Maele, B.; De Rijck, J.; Gijsbers, R.; Van den Haute, C.; Witvrouw, M.; Debyser, Z. Transient and stable knockdown of the integrase cofactor LEDGF/p75 reveals its role in the replication cycle of human immunodeficiency virus J. Virol. 2006, 80, 1886-1896
207. De Rijck, J.; Vandekerckhove, L.; Gijsbers, R.; Hombrouck, A.; Hendrix, J.; Vercammen, J.; Engelborghs, Y.; Christ, F.; Debyser, Z. Overexpression of the lens epithelium-derived growth factor/p75 integrase binding domain inhibits human immunodeficiency virus replication J. Virol. 2006, 80, 11498-11509
208. Al-Mawsawi, L. Q.; Christ, F.; Dayam, R.; Debyser, Z.; Neamati, N. Inhibitory profile of a LEDGF/p75 peptide against HIV-1 integrase: insight into integrase-DNA complex formation and catalysis FEBS Lett. 2008, 582, 1425-1430
209. Hayouka, Z.; Rosenbluh, J.; Levin, A.; Loya, S.; Lebendiker, M.; Veprintsev, D.; Kotler, M.; Hizi, A.; Loyter, A.; Friedler, A. Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium Proc. Nat. Acad. Sci. U.S.A. 2007, 104, 8316-8321
210. Hayouka, Z.; Levin, A.; Maes, M.; Hadas, E.; Shalev, D. E.; Volsky, D. J.; Loyter, A.; Friedler, A. Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370 Biochem. Biophys. Res. Commun. 2010, 394, 260-265
211. Hayouka, Z.; Hurevich, M.; Levin, A.; Benyamini, H.; Iosub, A.; Maes, M.; Shalev, D. E.; Loyter, A.; Gilon, C.; Friedler, A. Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein Bioorg. Med. Chem. 2010, 18, 8388-8395
212. Rhodes, D. I.; Peat, T. S.; Vandegraaff, N.; Jeevarajah, D.; Newman, J.; Martyn, J.; Coates, J. A.; Ede, N. J.; Rea, P.; Deadman, J. J. Crystal structures of novel allosteric peptide inhibitors of HIV integrase identify new interactions at the LEDGF binding site ChemBioChem 2011, 12, 2311-2315
213. Desimmie, B. A.; Humbert, M.; Lescrinier, E.; Hendrix, J.; Vets, S.; Gijsbers, R.; Ruprecht, R. M.; Dietrich, U.; Debyser, Z.; Christ, F. Phage display-directed discovery of LEDGF/p75 binding cyclic peptide inhibitors of HIV replication Mol. Ther. 2012, 20, 2064-2075
214. Bartholomeeusen, K.; De Rijck, J.; Busschots, K.; Desender, L.; Gijsbers, R.; Emiliani, S.; Benarous, R.; Debyser, Z.; Christ, F. Differential interaction of HIV-1 integrase and JPO2 with the C terminus of LEDGF/p75 J. Mol. Biol. 2007, 372, 407-421
215. Bartholomeeusen, K.; Gijsbers, R.; Christ, F.; Hendrix, J.; Rain, J. C.; Emiliani, S.; Benarous, R.; Debyser, Z.; De Rijck, J. Lens epithelium derived growth factor/p75 interacts with the transposase derived DDE domain of PogZ J. Biol. Chem. 2009, 284, 11467-11477
216. Maertens, G. N.; Cherepanov, P.; Engelman, A. Transcriptional co-activator p75 binds and tethers the Myc-interacting protein JPO2 to chromatin J. Cell Sci. 2006, 119, 2563-2571
217. Du, L.; Zhao, Y.; Chen, J.; Yang, L.; Zheng, Y.; Tang, Y.; Shen, X.; Jiang, H. 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. 2008, 375, 139-144
218. De Luca, L.; Barreca, M. L.; Ferro, S.; Christ, F.; Iraci, N.; Gitto, R.; Monforte, A. M.; Debyser, Z.; Chimirri, A. Pharmacophore-based discovery of small-molecule inhibitors of protein-protein interactions between HIV-1 integrase and cellular cofactor LEDGF/p75 Chem MedChem 2009, 4, 1311-1316
219. De Luca, L.; Ferro, S.; Gitto, R.; Barreca, M. L.; Agnello, S.; Christ, F.; Debyser, Z.; Chimirri, A. Small molecules targeting the interaction between HIV-1 integrase and LEDGF/p75 cofactor Bioorg. Med. Chem. 2010, 18, 7515-7521
220. Fan, X.; Zhang, F. H.; Al-Safi, R. I.; Zeng, L. F.; Shabaik, Y.; Debnath, B.; Sanchez, T. W.; Odde, S.; Neamati, N.; Long, Y. Q. Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: a scaffold hopping approach using salicylate and catechol groups Bioorg. Med. Chem. 2011, 19, 4935-4952
221. Peat, T. S.; Rhodes, D. I.; Vandegraaff, N.; Le, G.; Smith, J. A.; Clark, L. J.; Jones, E. D.; Coates, J. A.; Thienthong, N.; Newman, J.; Dolezal, O.; Mulder, R.; Ryan, J. H.; Savage, G. P.; Francis, C. L.; Deadman, J. J. Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design PLoS One 2012, 7, e40147
222. Hu, G.; Li, X.; Sun, X.; Lu, W.; Liu, G.; Huang, J.; Shen, X.; Tang, Y. Identification of old drugs as potential inhibitors of HIV-1 integrase-human LEDGF/p75 interaction via molecular docking J. Mol. Model. 2012, 18, 4995-5003
223. Christ, F.; Voet, A.; Marchand, A.; Nicolet, S.; Desimmie, B. A.; Marchand, D.; Bardiot, D.; Van der Veken, N. J.; Van Remoortel, B.; Strelkov, S. V.; De Maeyer, M.; Chaltin, P.; Debyser, Z. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication Nat. Chem. Biol. 2010, 6, 442-448
224. Christ, F.; Shaw, S.; Demeulemeester, J.; Desimmie, B. A.; Marchand, A.; Butler, S.; Smets, W.; Chaltin, P.; Westby, M.; Debyser, Z.; Pickford, C. Small-molecule inhibitors of the LEDGF/p75 binding site of integrase block HIV replication and modulate integrase multimerization Antimicrob. Agents Chemother. 2012, 56, 4365-4374
225. Tsantrizos, Y. S.; Boes, M.; Brochu, C.; Fenwick, C.; Malenfant, E.; Mason, S.; Pesant, M. Inhibitors of Human Immunodeficiency Virus Replication. PCT Int. Appl. WO 131350, 2007.
226. Kessl, J. J.; Jena, N.; Koh, Y.; Taskent-Sezgin, H.; Slaughter, A.; Feng, L.; de Silva, S.; Wu, L.; Le Grice, S. F.; Engelman, A.; Fuchs, J. R.; Kvaratskhelia, M. A multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors J. Biol. Chem. 2012, 287, 16801-16811
227. Tsiang, M.; Jones, G. S.; Niedziela-Majka, A.; Kan, E.; Lansdon, E. B.; Huang, W.; Hung, M.; Samuel, D.; Novikov, N.; Xu, Y.; Mitchell, M.; Guo, H.; Babaoglu, K.; Liu, X.; Geleziunas, R.; Sakowicz, R. New class of HIV-1 integrase (IN) inhibitors with a dual mode of action J. Biol. Chem. 2012, 287, 21189-21203
228. Kessl, J. J.; Li, M.; Ignatov, M.; Shkriabai, N.; Eidahl, J. O.; Feng, L.; Musier-Forsyth, K.; Craigie, R.; Kvaratskhelia, M. FRET analysis reveals distinct conformations of IN tetramers in the presence of viral DNA or LEDGF/p75 Nucleic Acids Res. 2011, 39, 9009-9022
229. De Luca, L.; Gitto, R.; Christ, F.; Ferro, S.; De Grazia, S.; Morreale, F.; Debyser, Z.; Chimirri, A. 4-[1-(4-Fluorobenzyl)-4-hydroxy-1 H -indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid as a prototype to develop dual inhibitors of HIV-1 integration process Antiviral Res. 2011, 92, 102-107
230. Tasara, T.; Maga, G.; Hottiger, M. O.; Hubscher, U. HIV-1 reverse transcriptase and integrase enzymes physically interact and inhibit each other FEBS Lett. 2001, 507, 39-44
231. Wilkinson, T. A.; Januszyk, K.; Phillips, M. L.; Tekeste, S. S.; Zhang, M.; Miller, J. T.; Le Grice, S. F.; Clubb, R. T.; Chow, S. A. Identifying and characterizing a functional HIV-1 reverse transcriptase-binding site on integrase J. Biol. Chem. 2009, 284, 7931-7939
232. Oz, I.; Avidan, O.; Hizi, A. Inhibition of the integrases of human immunodeficiency viruses type 1 and type 2 by reverse transcriptases Biochem. J. 2002, 361, 557-566
233. Oz-Gleenberg, I.; Avidan, O.; Goldgur, Y.; Herschhorn, A.; Hizi, A. Peptides derived from the reverse transcriptase of human immunodeficiency virus type 1 as novel inhibitors of the viral integrase J. Biol. Chem. 2005, 280, 21987-21996
234. Zawahir, Z.; Neamati, N. Inhibition of HIV-1 integrase activity by synthetic peptides derived from the HIV-1 HXB2 Pol region of the viral genome Bioorg. Med. Chem. Lett. 2006, 16, 5199-5202
235. Kogan, M.; Rappaport, J. HIV-1 accessory protein Vpr: relevance in the pathogenesis of HIV and potential for therapeutic intervention Retrovirology 2011, 8, 25
236. Bischerour, J.; Tauc, P.; Leh, H.; de Rocquigny, H.; Roques, B.; Mouscadet, J. F. The (52-96) C-terminal domain of Vpr stimulates HIV-1 IN-mediated homologous strand transfer of mini-viral DNA Nucleic Acids Res. 2003, 31, 2694-2702
237. Gleenberg, I. O.; Herschhorn, A.; Hizi, A. Inhibition of the activities of reverse transcriptase and integrase of human immunodeficiency virus type-1 by peptides derived from the homologous viral protein R (Vpr) J. Mol. Biol. 2007, 369, 1230-1243
238. Morellet, N.; Bouaziz, S.; Petitjean, P.; Roques, B. P. NMR structure of the HIV-1 regulatory protein VPR J. Mol. Biol. 2003, 327, 215-227
239. Suzuki, S.; Urano, E.; Hashimoto, C.; Tsutsumi, H.; Nakahara, T.; Tanaka, T.; Nakanishi, Y.; Maddali, K.; Han, Y.; Hamatake, M. Peptide HIV-1 integrase inhibitors from HIV-1 gene products J. Med. Chem. 2010, 53, 5356-5360
240. Suzuki, S.; Maddali, K.; Hashimoto, C.; Urano, E.; Ohashi, N.; Tanaka, T.; Ozaki, T.; Arai, H.; Tsutsumi, H.; Narumi, T.; Nomura, W.; Yamamoto, N.; Pommier, Y.; Komano, J. A.; Tamamura, H. Peptidic HIV integrase inhibitors derived from HIV gene products: structure-activity relationship studies Bioorg. Med. Chem. 2010, 18, 6771-6775
241. Rosenbluh, J.; Hayouka, Z.; Loya, S.; Levin, A.; Armon-Omer, A.; Britan, E.; Hizi, A.; Kotler, M.; Friedler, A.; Loyter, A. Interaction between HIV-1 Rev and integrase proteins: a basis for the development of anti-HIV peptides J. Biol. Chem. 2007, 282, 15743-15753
242. Grewe, B.; Uberla, K. The human immunodeficiency virus type 1 Rev protein: menage a trois during the early phase of the lentiviral replication cycle J. Gen. Virol. 2010, 91, 1893-1897
243. Levin, A.; Hayouka, Z.; Brack-Werner, R.; Volsky, D. J.; Friedler, A.; Loyter, A. Novel regulation of HIV-1 replication and pathogenicity: rev inhibition of integration Protein Eng., Des. Sel. 2009, 22, 753-763
244. Benyamini, H.; Loyter, A.; Friedler, A. A structural model of the HIV-1 Rev-integrase complex: the molecular basis of integrase regulation by Rev Biochem. Biophys. Res. Commun. 2011, 416, 252-257
245. Hayouka, Z.; Rosenbluh, J.; Levin, A.; Maes, M.; Loyter, A.; Friedler, A. Peptides derived from HIV-1 Rev inhibit HIV-1 integrase in a shiftide mechanism Biopolymers 2008, 90, 481-487
246. Levin, A.; Hayouka, Z.; Helfer, M.; Brack-Werner, R.; Friedler, A.; Loyter, A. Peptides derived from HIV-1 integrase that bind Rev stimulate viral genome integration PLoS One 2009, 4, e4155
247. Maroun, R. G.; Gayet, S.; Benleulmi, M. S.; Porumb, H.; Zargarian, L.; Merad, H.; Leh, H.; Mouscadet, J. F.; Troalen, F.; Fermandjian, S. Peptide inhibitors of HIV-1 integrase dissociate the enzyme oligomers Biochemistry 2001, 40, 13840-13848
248. Zhao, L.; O'Reilly, M. K.; Shultz, M. D.; Chmielewski, J. Interfacial peptide inhibitors of HIV-1 integrase activity and dimerization Bioorg. Med. Chem. Lett. 2003, 13, 1175-1177
249. Zhao, L.; Chmielewski, J. Inhibition of HIV-1 integrase dimerization and activity with crosslinked interfacial peptide Bioorg. Med. Chem. 2013, 21, 4041-4044
250. Al-Mawsawi, L. Q.; Fikkert, V.; Dayam, R.; Witvrouw, M.; Burke, T. R., Jr.; Borchers, C. H.; Neamati, N. Discovery of a small-molecule HIV-1 integrase inhibitor-binding site Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 10080-10085
251. Tsiang, M.; Jones, G. S.; Hung, M.; Mukund, S.; Han, B.; Liu, X.; Babaoglu, K.; Lansdon, E.; Chen, X.; Todd, J.; Cai, T.; Pagratis, N.; Sakowicz, R.; Geleziunas, R. Affinities between the binding partners of the HIV-1 integrase dimer-lens epithelium-derived growth factor (IN dimer-LEDGF) complex J. Biol. Chem. 2009, 284, 33580-33599
252. Tsiang, M.; Jones, G. S.; Hung, M.; Samuel, D.; Novikov, N.; Mukund, S.; Brendza, K. M.; Niedziela-Majka, A.; Jin, D.; Liu, X.; Mitchell, M.; Sakowicz, R.; Geleziunas, R. Dithiothreitol causes HIV-1 integrase dimer dissociation while agents interacting with the integrase dimer interface promote dimer formation Biochemistry 2011, 50, 1567-1581
253. Shkriabai, N.; Patil, S. S.; Hess, S.; Budihas, S. R.; Craigie, R.; Burke, T. R., Jr.; Le Grice, S. F.; Kvaratskhelia, M. Identification of an inhibitor-binding site to HIV-1 integrase with affinity acetylation and mass spectrometry Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 6894-6899
254. Kessl, J. J.; Eidahl, J. O.; Shkriabai, N.; Zhao, Z.; McKee, C. J.; Hess, S.; Burke, T. R., Jr.; Kvaratskhelia, M. An allosteric mechanism for inhibiting HIV-1 integrase with a small molecule Mol. Pharmacol. 2009, 76, 824-832
255. Du, L.; Zhao, Y. X.; Yang, L. M.; Zheng, Y. T.; Tang, Y.; Shen, X.; Jiang, H. L. Symmetrical 1-pyrrolidineacetamide showing anti-HIV activity through a new binding site on HIV-1 integrase Acta Pharmacol. Sin. 2008, 29, 1261-1267
256. Tintori, C.; Demeulemeester, J.; Franchi, L.; Massa, S.; Debyser, Z.; Christ, F.; Botta, M. Discovery of small molecule HIV-1 integrase dimerization inhibitors Bioorg. Med. Chem. Lett. 2012, 22, 3109-3114
257. Demeulemeester, J.; Tintori, C.; Botta, M.; Debyser, Z.; Christ, F. Development of an AlphaScreen-based HIV-1 integrase dimerization assay for discovery of novel allosteric inhibitors J. Biomol. Screening 2012, 17, 618-628
258. Wielens, J.; Headey, S. J.; Jeevarajah, D.; Rhodes, D. I.; Deadman, J.; Chalmers, D. K.; Scanlon, M. J.; Parker, M. W. Crystal structure of the HIV-1 integrase core domain in complex with sucrose reveals details of an allosteric inhibitory binding site FEBS Lett. 2010, 584, 1455-1462
259. Walsh, C. T.; Garneau-Tsodikova, S.; Gatto, G. J., Jr. Protein posttranslational modifications: the chemistry of proteome diversifications Angew. Chem., Int. Ed. 2005, 44, 7342-7372
260. Fukuda, H.; Sano, N.; Muto, S.; Horikoshi, M. Simple histone acetylation plays a complex role in the regulation of gene expression Briefings Funct. Genomics Proteomics 2006, 5, 190-208
261. Costi, R.; Di Santo, R.; Artico, M.; Miele, G.; Valentini, P.; Novellino, E.; Cereseto, A. Cinnamoyl compounds as simple molecules that inhibit p300 histone acetyltransferase J. Med. Chem. 2007, 50, 1973-1977
262. Toth, M.; Boros, I. M.; Balint, E. Elevated level of lysine 9-acetylated histone H3 at the MDR1 promoter in multidrug-resistant cells Cancer Sci. 2012, 103, 659-669
263. Hottiger, M. O.; Nabel, G. J. Viral replication and the coactivators p300 and CBP Trends Microbiol. 2000, 8, 560-565
264. Cereseto, A.; Manganaro, L.; Gutierrez, M. I.; Terreni, M.; Fittipaldi, A.; Lusic, M.; Marcello, A.; Giacca, M. Acetylation of HIV-1 integrase by p300 regulates viral integration EMBO J. 2005, 24, 3070-3081
265. Terreni, M.; Valentini, P.; Liverani, V.; Gutierrez, M. I.; Di Primio, C.; Di Fenza, A.; Tozzini, V.; Allouch, A.; Albanese, A.; Giacca, M.; Cereseto, A. GCN5-dependent acetylation of HIV-1 integrase enhances viral integration Retrovirology 2010, 7, 18
266. Topper, M.; Luo, Y.; Zhadina, M.; Mohammed, K.; Smith, L.; Muesing, M. A. Post-translational acetylation of the HIV-1 integrase carboxyl-terminal domain is dispensable for viral replication J. Virol. 2007, 81, 3012-3017
267. Allouch, A.; Di Primio, C.; Alpi, E.; Lusic, M.; Arosio, D.; Giacca, M.; Cereseto, A. The TRIM family protein KAP1 inhibits HIV-1 integration Cell Host Microbe 2011, 9, 484-495
268. Giannini, G.; Cabri, W.; Fattorusso, C.; Rodriquez, M. Histone deacetylase inhibitors in the treatment of cancer: overview and perspectives Future Med. Chem. 2012, 4, 1439-1460
269. Wiech, N. L.; Fisher, J. F.; Helquist, P.; Wiest, O. Inhibition of histone deacetylases: a pharmacological approach to the treatment of non-cancer disorders Curr. Top. Med. Chem. 2009, 9, 257-271
270. Chan, C. W.; Khachigian, L. M. DNAzymes and their therapeutic possibilities Intern. Med. J. 2009, 39, 249-251
271. Breaker, R. R.; Joyce, G. F. A DNA enzyme that cleaves RNA Chem. Biol. 1994, 1, 223-229
272. Chandrasekhar, K.; Malathhi, R. Non-Watson Crick base pairs might stabilize RNA structural motifs in ribozymes-a comparative study of group-I intron structures J. Biosci. 2003, 28, 547-555
273. Singh, N.; Ranjan, A.; Sur, S.; Chandra, R.; Tandon, V. Inhibition of HIV-1 integrase gene expression by 10-23 DNAzyme J. Biosci. 2012, 3, 493-502
274. Unwalla, H.; Banerjea, A. C. Novel mono- and di-DNAenzymes targeted to cleave TAT or TAT-REV RNA inhibit HIV-1 gene expression Antiviral Res. 2001, 51, 127-139
275. Butler, S. L.; Hansen, M. S.; Bushman, F. D. A quantitative assay for HIV DNA integration in vivo Nat. Med. 2001, 7, 631-634
276. Chun, T. W.; Carruth, L.; Finzi, D.; Shen, X.; DiGiuseppe, J. A.; Taylor, H.; Hermankova, M.; Chadwick, K.; Margolick, J.; Quinn, T. C.; Kuo, Y. H.; Brookmeyer, R.; Zeiger, M. A.; Barditch-Crovo, P.; Siliciano, R. F. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection Nature 1997, 387, 183-188
277. Levin, A.; Hayouka, Z.; Brack-Werner, R.; Volsky, D. J.; Friedler, A.;
278. Levin, A.; Hayouka, Z.; Friedler, A.; Brack-Werner, R.; Volsky, D. J.; Loyter, A. A novel role for the viral Rev protein in promoting resistance to superinfection by human immunodeficiency virus type 1 J. Gen. Virol. 2010, 91, 1503-1513
279. Levin, A.; Rosenbluh, J.; Hayouka, Z.; Friedler, A.; Loyter, A. Integration of HIV-1 DNA is regulated by interplay between viral rev and cellular LEDGF/p75 proteins Mol. Med. 2010, 16, 34-44
280. Levin, A.; Hayouka, Z.; Helfer, M.; Brack-Werner, R.; Friedler, A.; Loyter, A. Stimulation of the HIV-1 integrase enzymatic activity and cDNA integration by a peptide derived from the integrase protein Biopolymers 2010, 93, 740-751
281. Jung, A.; Maier, R.; Vartanian, J. P.; Bocharov, G.; Jung, V.; Fischer, U.; Meese, E.; Wain-Hobson, S.; Meyerhans, A. Recombination: multiply infected spleen cells in HIV patients Nature 2002, 418, 144
282. Levin, A.; Hayouka, Z.; Brack-Werner, R.; Volsky, D. J.; Friedler, A.; Loyter, A. Novel regulation of HIV-1 replication and pathogenicity: Rev inhibition of integration Protein Eng., Des. Sel. 2009, 22, 753-763
283. Levin, A.; Hayouka, Z.; Friedler, A.; Loyter, A. Specific eradication of HIV-1 from infected cultured cells AIDS Res. Ther. 2010, 7, 31