New class of HIV-1 integrase (IN) inhibitors with a dual mode of action

Journal of Biological Chemistry

Volumn 287, Issue 25, 2012, Pages 21189-21203

  Tsiang, Manuel ^a   Jones, Gregg S ^a   Niedziela Majka, Anita ^a   Kan, Elaine ^a   Lansdon, Eric B ^a   Huang, Wayne ^a   Hung, Magdeleine ^a   Samuel, Dharmaraj ^a   Novikov, Nikolai ^a   Xu, Yili ^a   Mitchell, Michael ^a   Guo, Hongyan ^a   Babaoglu, Kerim ^a   Liu, Xiaohong ^a   Geleziunas, Romas ^a   Sakowicz, Roman ^a  

^a GILEAD SCIENCES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALLOSTERIC INHIBITOR; ANTIVIRAL COMPOUND; ANTIVIRAL MECHANISMS; BINDING POCKETS; BIOCHEMICAL STUDIES; CONFORMATIONAL CHANGE; DIMER INTERFACE; DNA ASSEMBLIES; DUAL MODES; ENZYMATIC ACTIVITIES; HIV-1 INTEGRASE; LENS EPITHELIUM-DERIVED GROWTH FACTORS; LONG TERMINAL REPEATS; PROCESSING STEPS; VIRAL DNA;

ACETIC ACID;

DNA;

AMPRENAVIR; EFAVIRENZ; INTEGRASE; INTEGRASE INHIBITOR; LENS EPITHELIUM DERIVED GROWTH FACTOR; NEW DRUG; RALTEGRAVIR; TERT BUTOXY (4 PHENYLQUINOLIN 3 YL)ACETIC ACID; UNCLASSIFIED DRUG; VIRUS DNA;

3' UNTRANSLATED REGION; ANTIVIRAL ACTIVITY; ARTICLE; BINDING SITE; CELL JUNCTION; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; DNA PROTEIN COMPLEX; DRUG PROTEIN BINDING; DRUG STRUCTURE; ENZYME ACTIVITY; ENZYME INHIBITION; HUMAN; HUMAN CELL; LONG TERMINAL REPEAT; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; VIRUS ASSEMBLY;

ACETIC ACIDS; ADAPTOR PROTEINS, SIGNAL TRANSDUCING; CELL LINE; CHROMATIN; DNA, VIRAL; HIV INFECTIONS; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HIV-1; HUMANS; QUINOLINES; TRANSCRIPTION FACTORS; VIRUS INTEGRATION;

EID: 84862271587     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M112.347534     Document Type: Article

References (64)

1. Bushman, F. D., and Craigie, R. (1991) Activities of human immunodeficiency virus (HIV) integration protein in vitro: specific cleavage and integration of HIV DNA. Proc. Natl. Acad. Sci. U.S.A. 88, 1339-1343 (Pubitemid 21916220)
2. Craigie, R., Mizuuchi, K., Bushman, F. D., and Engelman, A. (1991) A rapid in vitro assay for HIV DNA integration. Nucleic Acids Res. 19, 2729-2734 (Pubitemid 21896911)
3. Hazuda, D. J., Hastings, J. C., Wolfe, A. L., and Emini, E. A. (1994) A novel assay for the DNA strand-transfer reaction of HIV-1 integrase. Nucleic Acids Res. 22, 1121-1122 (Pubitemid 24162181)
4. Savarino, A. (2006) A historical sketch of the discovery and development of HIV-1 integrase inhibitors. Expert Opin. Investig. Drugs 15, 1507-1522
5. Al-Mawsawi, L. Q., Al-Safi, R. I., and Neamati N. (2008) Anti-infectives: clinical progress of HIV-1 integrase inhibitors. Expert Opin. Emerg. Drugs 13, 213-225 (Pubitemid 351958439)
6. Cooper, D. A., Gatell, J., Rockstroh, J., Katlama, C., Yeni, P., Lazzarin, A., Xu, X., Isaacs, R., Teppler, H., Nguyen, B. Y., and the BENCHMRK-1 Study Group (2008) 15th Conference on Retroviruses and Opportunistic Infections, Boston, February 3-6, 2008, Abstr. 788, p. 357, CROI and UC San Diego School of Medicine, Alexandria, VA
7. Steigbigel, R., Kumar, P., Eron, J., Schechter, M., Markowitz, M., Loutfy, M., Zhao, J., Isaacs, R., Nguyen, B. Y., Teppler, H., and the BENCHMRK-2 Study Group (2008) 15th Conference on Retroviruses and Opportunistic Infections, Boston, February 3-6, 2008, Abstr. 789, p. 357, CROI and UC San Diego School of Medicine, Alexandria, VA
8. 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., Campbell, H., Strohmaier, K. M., Wan, H., Danovich, R. M., Teppler, H., and Protocol 004 Part II Study Team (2009) Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatmentnaive patients with HIV-1 infection. J. Acquir. Immune Defic. Syndr. 52, 350-356
9. Zolopa, A. R., Berger, D. S., Lampiris, H., Zhong, L., Chuck, S. L., Enejosa, J. V., Kearney, B. P., and Cheng, A. K. (2010) Activity of elvitegravir, a once-daily integrase inhibitor, against resistant HIV type 1: results of a phase 2, randomized, controlled, dose-ranging clinical trial. J. Infect. Dis. 201, 814-822
10. Shimura, K., and Kodama, E. N. (2009) Elvitegravir: a new HIV integrase inhibitor. Antivir. Chem Chemother. 20, 79-85
11. Mathias, A., Lee, M., Callebaut, C., Xu, L., Tsai, L., Murray, B., Liu, H., Yale, K., Warren, D., and Kearney. B. (2009) 16th Conference on Retroviruses and Opportunistic Infections, Montreal, February 8-11, 2009, Abstr. 40, p. 79, CROI and UC San Diego School of Medicine, Alexandria, VA
12. Min, S., Song, I., Borland, J., Chen, S., Lou, Y., Fujiwara, T., and Piscitelli, S. C. (2010) Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob. Agents Chemother. 54, 254-258
13. 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., and Fujiwara, T. (2011) In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob. Agents Chemother. 55, 813-821
14. DeJesus E., Cohen, C., Elion, R., Ortiz, R., Maroldo, L., Franson, S., et al. (2007) 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention, Sydney, July 22-25, 2007, Abstr. TUPEB032, International AIDS Society
15. Wai, J., Fisher, T., Embrey, M., Egbertson, M., Vacca, J., Hazuda, D., Miller, M., Witmer, M., Gabryelski, L., and Lyle, T. (2007) 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, February 25-28, 2007, Abstr. 87, p. 96, CROI and UC San Diego School of Medicine, Alexandria, VA
16. 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., and Marcelin, A. G. (2008) Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob. Agents Chemother. 52, 1351-1358 (Pubitemid 351521998)
17. Métifiot, M., Marchand, C., Maddali, K., and Pommier, Y. (2010) Resistance to integrase inhibitors. Viruses 2, 1347-1366
18. Al-Mawsawi, L. Q., and Neamati N. (2011) Allosteric inhibitor development targeting HIV-1 integrase. Chem. Med. Chem. 6, 228-241
19. Engelman, A., Englund, G., Orenstein, J. M., Martin, M. A., and Craigie, R. (1995) Multiple effects of mutations in human immunodeficiency virus type 1 integrase on viral replication. J. Virol. 69, 2729-2736
20. Zheng, R., Jenkins, T. M., and Craigie, R. (1996) Zinc folds the N-terminal domain of HIV-1 integrase, promotes multimerization, and enhances catalytic activity. Proc. Natl. Acad. Sci. U.S.A. 93, 13659-13664 (Pubitemid 26424175)
21. Cai, M., Zheng, R., Caffrey, M., Craigie, R., Clore, G. M., and Gronenborn, A. M. (1997) Solution structure of the N-terminal zinc binding domain of HIV-1 integrase. Nat. Struct. Biol. 4, 567-577 (Pubitemid 27282153)
22. Wu, X., Liu, H., Xiao, H., Conway, J. A., Hehl, E., Kalpana, G. V., Prasad, V., Kappes, J. C. (1999) Human immunodeficiency virus type 1 integrase protein promotes reverse transcription through specific interactions with the nucleoprotein reverse transcription complex. J. Virol. 73, 2126-2135 (Pubitemid 29098117)
23. Carayon, K., Leh, H., Henry, E., Simon, F., Mouscadet, J. F., Deprez, E. (2010) A cooperative and specific DNA-binding mode of HIV-1 integrase depends on the nature of the metallic cofactor and involves the zinccontaining N-terminal domain. Nucleic Acids Res. 38, 3692-3708
24. Du, L., Shen, L., Yu, Z., Chen, J., Guo, Y., Tang, Y., Shen, X., and Jiang, H. (2008) Hyrtiosal, from the marine sponge Hyrtios erectus, inhibits HIV-1 integrase binding to viral DNA by a new inhibitor binding site. Chem. Med. Chem. 3, 173-180
25. Lodi, P. J., Ernst, J. A., Kuszewski, J., Hickman, A. B., Engelman, A., Craigie, R., Clore, G. M., and Gronenborn, A. M. (1995) Solution structure of the DNA binding domain of HIV-1 integrase. Biochemistry 34, 9826-9833
26. Lutzke, R. A., Vink, C., and Plasterk, R. H. (1994) Characterization of the minimal DNA-binding domain of the HIV integrase protein. Nucleic Acids Res. 22, 4125-4131 (Pubitemid 24322714)
27. Williams, K. L., Zhang, Y., Shkriabai, N., Karki, R. G., Nicklaus, M. C., Kotrikadze, N., Hess, S., Le Grice, S. F., Craigie, R., Pathak, V. K., and Kvaratskhelia, M. (2005) Mass spectrometric analysis of the HIV-1 integrase-pyridoxal 5′-phosphate complex reveals a new binding site for a nucleotide inhibitor. J. Biol. Chem. 280, 7949-7955 (Pubitemid 40349692)
28. Maroun, R. G., Gayet, S., Benleulmi, M. S., Porumb, H., Zargarian, L., Merad, H., Leh, H., Mouscadet, J. F., Troalen, F., and Fermandjian, S. (2001) Peptide inhibitors of HIV-1 integrase dissociate the enzyme oligomers. Biochemistry 40, 13840-13848 (Pubitemid 33078852)
29. Zhao, L., O'Reilly, M. K., Shultz, M. D., Chmielewski, J. (2003) Interfacial peptide inhibitors of HIV-1 integrase activity and dimerization. Bioorg. Med. Chem. Lett. 13, 1175-1177 (Pubitemid 36331825)
30. Li, H. Y., Zawahir, Z., Song, L. D., Long, Y. Q., and Neamati, N. (2006) Sequence-based design and discovery of peptide inhibitors of HIV-1 integrase: insight into the binding mode of the enzyme. J. Med. Chem. 49, 4477-4486 (Pubitemid 44162674)
31. Molteni, V., Greenwald, J., Rhodes, D., Hwang, Y., Kwiatkowski, W., Bushman, F. D., Siegel, J. S., and Choe, S. (2001) Acta Crystallogr. D Biol. Crystallogr. 57, 536-544
32. Al-Mawsawi, L. Q., Fikkert, V., Dayam, R., Witvrouw, M., Burke, T. R., Jr., Borchers, C. H., and Neamati, N. (2006) Discovery of a small-molecule HIV-1 integrase inhibitor-binding site. Proc. Natl. Acad. Sci. U.S.A. 103, 10080-10085 (Pubitemid 43993626)
33. Kessl, J. J., Eidahl, J. O., Shkriabai, N., Zhao, Z., McKee, C. J., Hess, S., Burke, T. R., Jr., and Kvaratskhelia, M. (2009) An allosteric mechanism for inhibiting HIV-1 integrase with a small molecule. Mol. Pharmacol. 76, 824-832
34. Du, L., Zhao, Y. X., Yang, L. M., Zheng, Y. T., Tang, Y., Shen, X., and Jiang, H. L. (2008) Symmetrical 1-pyrrolidineacetamide showing anti-HIV activity through a new binding site on HIV-1 integrase. Acta Pharmacol. Sin. 29, 1261-1267
35. McKee, C. J., Kessl, J. J., Shkriabai, N., Dar, M. J., Engelman, A., and Kvaratskhelia, M. (2008) Dynamic modulation of HIV-1 integrase structure and function by cellular lens epithelium-derived growth factor (LEDGF) protein. J. Biol. Chem. 283, 31802-31812
36. 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., and Geleziunas, R. (2011) Dithiothreitol causes HIV-1 integrase dimer dissociation while agents interacting with the integrase dimer interface promote dimer formation. Biochemistry 50, 1567-1581
37. Cherepanov, P., Maertens, G., Proost, P., Devreese, B., Van Beeumen, J., Engelborghs, Y., De Clercq, E., and Debyser, Z. (2003) HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J. Biol. Chem. 278, 372-381 (Pubitemid 36043586)
38. Maertens, G., Cherepanov, P., Pluymers, W., Busschots, K., De Clercq, E., Debyser, Z., and Engelborghs, Y. (2003) LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. J. Biol. Chem. 278, 33528-33539 (Pubitemid 37055807)
39. Cherepanov, P., Devroe, E., Silver, P. A., and Engelman, A. (2004) Identification of an evolutionarily conserved domain in human lens epitheliumderived growth factor/transcriptional co-activator p75 (LEDGF/p75) that binds HIV-1 integrase. J. Biol. Chem. 279, 48883-48892 (Pubitemid 39625769)
40. Emiliani, S., Mousnier, A., Busschots, K., Maroun, M., Van Maele, B., Tempé, D., Vandekerckhove, L., Moisant, F., Ben-Slama, L., Witvrouw, M., Christ, F., Rain, J. C., Dargemont, C., Debyser, Z., and Benarous, R. (2005) Integrase mutants defective for interaction with LEDGF/p75 are impaired in chromosome tethering and HIV-1 replication. J. Biol. Chem. 280, 25517-25523 (Pubitemid 40962257)
41. Ciuffi, A., Llano, M., Poeschla, E., Hoffmann, C., Leipzig, J., Shinn, P., Ecker, J. R., and Bushman, F. (2005) A role for LEDGF/p75 in targeting HIV DNA integration. Nature Medicine 11, 1287-1289 (Pubitemid 41752906)
42. Cherepanov, P., Sun, Z. Y., Rahman, S., Maertens, G., Wagner, G., and Engelman, A. (2005) Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75. Nat. Struct. Mol. Biol. 12, 526-532 (Pubitemid 43085883)
43. Cherepanov, P., Ambrosio, A. L., Rahman, S., Ellenberger, T., and Engelman, A. (2005) Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc. Natl. Acad. Sci. U.S.A. 102, 17308-17313 (Pubitemid 41740862)
44. Vandekerckhove, L., Christ, F., Van Maele, B., De Rijck, J., Gijsbers, R., Van den Haute, C., Witvrouw, M., and Debyser, Z. (2006) Transient and stable knockdown of the integrase cofactor LEDGF/p75 reveals its role in the replication cycle of human immunodeficiency virus. J. Virol. 80, 1886-1896 (Pubitemid 43228728)
45. Llano, M., Saenz, D. T., Meehan, A., Wongthida, P., Peretz, M., Walker, W. H., Teo, W., and Poeschla, E. M. (2006) An essential role for LEDGF/p75 in HIV integration. Science 314, 461-464 (Pubitemid 44628966)
46. De Rijck, J., Vandekerckhove, L., Gijsbers, R., Hombrouck, A., Hendrix, J., Vercammen, J., Engelborghs, Y., Christ, F., and Debyser, Z. (2006) Over-expression of the lens epithelium-derived growth factor/p75 integrase binding domain inhibits human immunodeficiency virus replication. J. Virol. 80, 11498-11509 (Pubitemid 44788865)
47. Hou, Y., McGuinness, D. E., Prongay, A. J., Feld, B., Ingravallo, P., Ogert, R. A., Lunn, C. A., and Howe, J. A. (2008) Screening for antiviral inhibitors of the HIV integrase-LEDGF/p75 interaction using the AlphaScreen luminescent proximity assay. J. Biomol. Screen 13, 406-414 (Pubitemid 351793981)
48. Du, L., Zhao, Y., Chen, J., Yang, L., Zheng, Y., Tang, Y., Shen, X., and Jiang, H. (2008) 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, 139-144
49. De Luca, L., Barreca, M. L., Ferro, S., Christ, F., Iraci, N., Gitto, R., Monforte, A. M., Debyser, Z., and Chimirri, A. (2009) Pharmacophore-based discovery of small-molecule inhibitors of protein-protein interactions between HIV-1 integrase and cellular cofactor LEDGF/p75. Chem. Med. Chem. 4, 1311-1316
50. 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., and Debyser, Z. (2010) Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat. Chem. Biol. 6, 442-448
51. Tsantrizos, Y. S., Boes, M., Brochu, C., Fenwick, C., Malenfant, E., Mason, S., and Pesant, M. (November 22, 2007) Inhibitors of Human Immunodeficiency Virus Replication. International patent application WO 2007/131350 A1
52. Tsantrizos, Y. S., Bailey, M. D., Bilodeau, F., Carson, R. J., Coulombe, R., Fader, L., Halmos, T., Kawai, S., Landry, S., Laplante, S., Morin, S., Parisien, M., Poupart, M. A., and Simoneau, B. (May 22, 2009) Inhibitors of Human Immunodeficiency Virus Replication. International patent application WO 2009/062285 A1
53. Tsantrizos, Y. S., Bailey, M. D., Bilodeau, F., Carson, R. J., Fader, L., Halmos, T., Kawai, S., Landry, S., Laplante, S., and Simoneau, B. (May 22, 2009) Inhibitors of Human Immunodeficiency Virus Replication. International patent application WO 2009/062289 A1
54. 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., and Geleziunas, R. (2009) Affinities between the binding partners of the HIV-1 integrase dimer-lens epithelium-derived growth factor (IN dimer-LEDGF) complex. J. Biol. Chem. 284, 33580-33599
55. Jones, G. S., Yu, F., Zeynalzadegan, A., Hesselgesser, J., Chen, X., Chen, J., Jin, H., Kim, C. U., Wright, M., Geleziunas, R., and Tsiang, M. (2009) Preclinical evaluation of GS-9160, a novel inhibitor of human immunodeficiency virus type 1 integrase. Antimicrob. Agents Chemother. 53, 1194-1203
56. Otwinowski, Z. M., and Minor, W. (1997) Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307-326
57. Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L. W., Kapral, G. J., Grosse-Kunstleve, R. W., McCoy, A. J., Moriarty, N. W., Oeffner, R., Read, R. J., Richardson, D. C., Richardson, J. S., Terwilliger, T. C., and Zwart P. H. (2010) PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D. Biol. Crystallogr. 66, 213-221
58. Emsley, P., and Cowtan, K. (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr. D. Biol. Crystallogr. 60, 2126-2132 (Pubitemid 41742764)
59. Wang, Y., Klock, H., Yin, H., Wolff, K., Bieza, K., Niswonger, K., Matzen, J., Gunderson, D., Hale, J., Lesley, S., Kuhen, K., Caldwell, J., and Brinker, A. (2005) Homogeneous high-throughput screening assays for HIV-1 integrase 3β-processing and strand transfer activities. J. Biomol. Screen 10, 456-462 (Pubitemid 41233224)
60. Svarovskaia, E. S., Barr, R., Zhang, X., Pais, G. C., Marchand, C., Pommier, Y., Burke, T. R., Jr., and Pathak, V. K. (2004) Azido-containing diketo acid derivatives inhibit human immunodeficiency virus type 1 integrase in vivo and influence the frequency of deletions at two long-terminal-repeat-circle junctions. J. Virol. 78, 3210-3222 (Pubitemid 38568261)
61. Hombrouck, A., De Rijck, J., Hendrix, J., Vandekerckhove, L., Voet, A., De Maeyer, M., Witvrouw, M., Engelborghs, Y., Christ, F., Gijsbers, R., and Debyser, Z. (2007) Virus evolution reveals an exclusive role for LEDGF/p75 in chromosomal tethering of HIV. PLoS Pathog. 3, e47
62. Lataillade, M., Chiarella, J., and Kozal, M. J. (2007) Natural polymorphism of the HIV-1 integrase gene and mutations associated with integrase inhibitor resistance. Antiviral Ther. 12, 563-570 (Pubitemid 47041156)
63. Kessl, J. J., Li, M., Ignatov, M., Shkriabai, N., Eidahl, J. O., Feng, L., Musier-Forsyth, K., Craigie, R., and Kvaratskhelia, M. (2011) FRET analysis reveals distinct conformations of IN tetramers in the presence of viral DNA or LEDGF/p75. Nucleic Acids Res. 39, 9009-9022
64. Kessl, 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. (March 21, 2012) Multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors. J. Biol. Chem. 10.1074/jbc.M112.354373