Clinical Use of Inhibitors of HIV-1 Integration: Problems and Prospects

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Abstract


The HIV-1 integrase enzyme is responsible for one of the key stages of retroviral replication; it acts as a catalyst for the integration of viral cDNA into the cell’s genome. Inhibitors of HIV-1 integration have been under development for over 10 years; yet, only one integration inhibitor, raltegravir, has been approved for clinical use so far. Raltegravir binds two metal ions in the enzyme’s active centre and blocks one of the integration stages: the strand transfer. Unfortunately, the clinical use of raltegravir results in the development of viral resistance among some patients. Several more HIV-1 integration inhibitors are undergoing clinical trials at the moment. However, the structure and mechanism of action of those are similar to raltegravir, which results in the emergence of cross resistance with raltegravir. The present review is focused on the history of the development and clinical trials of raltegravir and its analogues, the problems connected with the emergence of viral resistance to integration inhibitors, and the prospect of their future clinical use.

Clinical Use of Inhibitors of HIV-1 Integration: Problems and Prospects

S P Korolev

Lomonosov Moscow State University

Email: spkorolev@mail.ru
Department of Chemistry

Yu Yu Agapkina

Lomonosov Moscow State University

Department of Chemistry

M B Gottikh

Lomonosov Moscow State University; Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University

Department of Chemistry

  1. http://www.unaids.org/ru
  2. Simon V., Ho D.D., Abdool Karim Q. // Lancet. 2006. V. 368. № 9534. P. 489-504.
  3. Turner B.G., Summers M.F. // J. Mol. Biol. 1999. V. 285. P. 1-32.
  4. Miller M.D., Farnet C.M., Bushman F.D. // J. Virol. 1997. V. 71. P 5382-5390.
  5. Piller S.C., Caly L., Jans D.A. // Cur. Drug. Targets. 2003. V. 4. № 5. P 409-429.
  6. Li L., Olvera J., Yoder K., Mitchell R.S., Butler S.L., Lieber M., Martin S.L., Bushman F.D. // EMBO J. 2001. V. 20. P. 3272-3281.
  7. Farnet C.M., Bushman F.D. // Cell. 1997. V. 88. P 483-492.
  8. Lin C.W., Engelman A. // J. Virol. 2003. V. 77. P 5030-5036.
  9. Vandegraaff N., Devroe E., Turlure F., Silver P.A., Engelman A. // Virology. 2006. V. 346. P 415-426.
  10. Marcelin A.G., Ceccherini-Silberstein F., Perno C.F., Calvez V. // Curr. Opin. HIV AIDS. 2009. V. 4. № 6. P. 531-537.
  11. FDA approves raltegravir tablets // AIDS Patient Care STDS. 2007. V. 21. № 11. P. 889.
  12. Cara A., Guarnaccia F., Reitz M.S. Jr., Gallo R.C., Lori F. // Virology. 1995. V. 208. P. 242-248.
  13. Ramkumar K., Serrao E., Odde S., Neamati N. // Med. Res. Rev. 2010. V. 30. № 5. P. 750-814.
  14. Mouscadet J.F., Delelis O., Marcelin A.G., Tchertanov L. // Drug Resist Updat. 2010. V. 13. № 4-5. P. 139-150.
  15. De Clercq E. // Curr. Opin. Pharmacol. 2010. V. 10. № 5. P. 507-515.
  16. Al-Mawsawi L.Q., Al-Safi R.I., Neamati N. // Expert Opin. Emerg. Drugs. 2008. V. 13. № 2. P 213-225.
  17. Gatell J.M. // Eur. J. Med. Res. 2009. V. 14. P. 30-35.
  18. Serrao E., Odde S., Ramkumar K., Neamati N. // Retrovirology. 2009. V. 6. № 25. Р
  19. Prikazchikova T.A., Sycheva A.M., Agapkina Yu.Yu., Aleksandrov D.A., Gottikh M.B. // Russ. Chem. Rev. 2008. V. 77 (5). P. 421-434.
  20. Agapkina Yu. Yu., Prikazchikova T. A., Smolov M.A., Gottikh M.B. // Uspekhi Biol. Khimii. V. 45. P. 87-122.
  21. Delelis O., Carayon K., Saïb A., Deprez E., Mouscadet J.-F. // Retrovirology. 2008. V. 5. P. 114.
  22. Poeschla E.M. // Cell Mol. Life Sci. 2008. V. 65. № 9. P. 1403-1424.
  23. Zheng R., Jenkins T.M., Craigie R. // Proc. Natl. Acad. Sci. USA. 1996. V. 93. № 24. P 13659-13664.
  24. Gallay P., Hope T., Chin D., Trono D. // Proc. Natl. Acad. Sci. USA. 2005. V. 94. P. 9825-9830.
  25. Podtelezhnikov A.A., Gao K., Bushman F.D., McCammon J.A. // Biopolymers. 2003. V. 68. № 1. P 110-120.
  26. Wielens J., Crosby I.T., Chalmers D.K. // J. Comput. Aided Mol. Des. 2005. V. 19. № 5. P 301-317.
  27. Ren G., Gao K., Bushman F.D., Yeager M. // J. Mol. Biol. 2007. V. 366. № 1. P. 286-294.
  28. Hare S., Gupta S.S., Valkov E., Engelman A., Cherepanov P // Nature. 2010. V. 464. № 7286. P 232-236.
  29. Delelis O., Carayon K., Guiot E., Leh H., Tauc P., Brochon J.C., Mouscadet J.-F., Deprez E. // J. Biol. Chem. 2008. V. 283. № 41. P. 27838-27849.
  30. Knyazhanskaya E.S., Smolov M.A., Kondrashina O.V., Gottikh M.B. // Acta Naturae. 2009. V. 1. № 2. P. 78-80.
  31. Sinha S., Pursley M.H., Grandgenett D.P // J. Virol. 2002. V. 76. P. 3105-3113.
  32. van Maele B., Debyser Z. // AIDS Rev. 2005. V. 7. P 26-43.
  33. Yu F., Jones G.S., Hung M., Wagner A.H., MacArthur H.L., Liu X., Leavitt S., McDermott M.J., Tsiang M. // Biochemistry. 2007. V. 46. № 10. P 2899-2908.
  34. Hazuda D.J., Felock P., Witmer M., Wolfe A., Stillmock K., Grobler J.A., Espeseth A., Gabryelski L., Schleif W., Blau C., et al. // Science. 2000. V. 287. № 5453. P. 646-650.
  35. 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., et al. // Proc. Natl. Acad. Sci. USA. 2004. V. 101. № 31. P. 11233-11238.
  36. Summa V., Petrocchi A., Matassa V.G., Gardelli C., Muraglia E., Rowley M., Paz O.G., Laufer R., Monteagudo E., Pace P. // J. Med. Chem. 2006. V. 49. № 23. P. 6646-6649.
  37. 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., et al. // Bioorg. Med. Chem. Lett. 2006. V. 16. № 11. P. 2900-2904.
  38. Espeseth A.S., Felock P., Wolfe A., Witmer M., Grobler J., Anthony N., Egbertson M., Melamed J.Y., Young S., Hamill Т., et al. // Proc. Natl. Acad. Sci. USA. 2000. V. 97. № 21. P. 11244-11249.
  39. Goldgur Y., Craigie R., Cohen G.H., Fujiwara Т., Yoshinaga Т., Fujishita Т., Sugimoto H., Endo Т., Murai H., Davies D.R. // Proc. Natl. Acad. Sci. USA. 1999. V. 96. № 23. P. 13040-13043.
  40. Grobler J.A., Stillmock K., Hu B., Witmer M., Felock P., Espeseth A.S., Wolfe A., Egbertson M., Bourgeois M., Jeffrey Melamed J., et al. // Proc. Natl. Acad. Sci. USA. 2002. V. 99. № 10. P. 6661-6666.
  41. Marchand C., Zhang X., Pais G.C.G., Cowansage K., Neamati N., Burke T.R., Pommier Y. // J. Biol. Chem. 2002. V. 277. P. 12596-12603.
  42. Billich A. // Curr. Opin. Investig. Drugs. 2003. V. 4. № 2. P. 206-209.
  43. 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., et al. // J. Med. Chem. 2003. V. 46. № 4. P. 453-456.
  44. Cotelle P. // Recent Patents on Anti-Infective Drug Discovery. 2006. V. 1. P. 1-15.
  45. Petrocchi A., Koch U., Matassa V.G., Pacini B., Stillmock K.A., Summa V. // Bioorg. Med. Chem. Lett. 2007. V. 17. № 2. P. 350-353.
  46. Pace P., Di Francesco M.E., Gardelli C., Harper S., Muraglia E., Nizi E., Orvieto F., Petrocchi A., Poma M., Rowley M., et al. // J. Med. Chem. 2007. V. 50. № 9. P. 2225-2239.
  47. Gardelli C., Nizi E., Muraglia E., Crescenzi B., Ferrara M., Orvieto F., Pace P., Pescatore G., Poma M., Ferreira Mdel R., et al. // J. Med. Chem. 2007. V. 50. № 20. P. 4953-4975.
  48. Summa V., Petrocchi A., Bonelli F., Crescenzi B., Donghi M., Ferrara M., Fiore F., Gardelli C., Gonzalez Paz O., Hazuda D.J., et al. // J. Med. Chem. 2008. V. 51. № 18. P. 5843-5855.
  49. Kassahun K., McIntosh I., Cui D., Hreniuk D., Merschman S., Lasseter K., Azrolan N., Iwamoto M., Wagner J.A., Wenning L.A. // Drug. Metab. Dispos. 2007. V. 35. № 9. P. 1657-1663.
  50. Iwamoto M., Wenning L.A., Petry A.S., Laethem M., De Smet M., Kost J.T., Merschman S.A., Strohmaier K.M., Ramael S., Lasseter K.C., et al. // Clin. Pharmacol. Ther. 2008. V. 83. № 2. P. 293-299.
  51. Markowitz M., Morales-Ramirez J.O., Nguyen B.Y., Kovacs C.M., Steigbigel R.T., Cooper D.A., Liporace R., Schwartz R., Isaacs R., Gilde L.R., et al. // J. Acquir. Immune. Defic. Syndr. 2006. V. 43. № 5. P. 509-515.
  52. Schafer J.J., Squires K.E. // Ann. Pharmacother. 2010. V. 44. № 1. P. 145-156.
  53. Ménard A., Solas C., Mokthari S., Bregigeon S., Drogoul M.P., Tamalet C., Lacarelle B., Martin I.P. // AIDS. 2009. V. 23. № 7. P. 869-871.
  54. 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. // Lancet. 2007. V. 369. № 9569. P. 1261-1269.
  55. Steigbigel R.T., Cooper D.A., Teppler H., Eron J. J., Gatell J.M., Kumar P.N., Rockstroh J.K., Schechter M., Katlama C., Markowitz M., et al. // Clin. Infect. Dis. 2010. V. 50. № 4. P. 605-612.
  56. 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., et al. // J. Acquir. Immune. Defic. Syndr. 2007. V. 46. № 2. P. 125-133.
  57. 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., et al. // Lancet. 2009. V. 374. № 9692. P. 796-806.
  58. Towner W., Klein D., Kerrigan H.L., Follansbee S., Yu K., Horberg M. // J. Acquir. Immune. Defic. Syndr. 2009. V. 51. № 4. P. 367-373.
  59. FDA notifications. Raltegravir indication extended for treatment-naive patients // AIDS Alert. 2009. V. 24. № 8. P. 93.
  60. Cooper D.A., Steigbigel R.T., Gatell J.M., Rockstroh J.K., Katlama C., Yeni P., Lazzarin A., Clotet B., Kumar P.N., Eron J.E., et al. // N. Engl. J. Med. 2008. V. 359. № 4. P. 355-365.
  61. Malet I., Delelis O., Valantin M.A., Montes B., Soulie C., Wirden M., Tchertanov L., Peytavin G., Reynes J., Mouscadet J.-F., et al. // Antimicrob. Agents. Chemother. 2008. V. 52. № 4. P. 1351-1358.
  62. Delelis O., Malet I., Na L., Tchertanov L., Calvez V., Marcelin A.G., Subra F., Deprez E., Mouscadet J.-F. // Nucleic. Acids Res. 2009. V. 37. № 4. P. 1193-1201.
  63. 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., et al. // Bioorg. Med. Chem. Lett. 2008. V. 18. № 16. P. 4581-4583.
  64. Di Francesco M.E., Pace P., Fiore F., Naimo F., Bonelli F., Rowley M., Summa V. // Bioorg. Med. Chem. Lett. 2008. V. 18. № 8. P. 2709-2713.
  65. Wai J.S., Kim B., Fisher T.E., Zhuang L., Embrey M.W., Williams P.D., Staas D.D., Culberson C., Lyle T.A., Vacca J.P., et al. // Bioorg. Med. Chem. Lett. 2007. V. 17. № 20. P. 5595-5599.
  66. Muraglia E., Kinzel O., Gardelli C., Crescenzi B., Donghi M., Ferrara M., Nizi E., Orvieto F., Pescatore G., Laufer R., et al. // J. Med. Chem. 2008. V. 51. № 4. P. 861-874.
  67. Jin H., Wright M., Pastor R., Mish M., Metobo S., Jabri S., Lansdown R., Cai R., Pyun P., Tsiang M., et al. // Bioorg. Med. Chem. Lett. 2008. V. 18. № 4. P. 1388-1391.
  68. 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., et al. // Antimicrob. Agents Chemother. 2008. V. 52. № 3. P. 901-908.
  69. Reddy Y.S., Min S.S., Borland J., Song I., Lin J., Palleja S., Symonds W.T. // Antimicrob. Agents Chemother. 2007. V. 51. № 12. P. 4284-4289.
  70. Min S., Song I., Borland J., Chen S., Lou Y., Fujiwara Т., Piscitelli S.C. // Antimicrob. Agents Chemother. 2010. V. 54. № 1. P. 254-258.
  71. Vandeckerckhove L. // Curr. Opin. Invest. Drugs. 2010. V. 11. P. 203-212.
  72. Sato M., Motomura Т., Aramaki H., Matsuda Т., Yamashita M., Ito Y., Kawakami H., Matsuzaki Y., Watanabe W., Yamataka K., et al. // J. Med. Chem. 2006. V. 49. № 5. P. 1506-1508.
  73. Sato M., Kawakami H., Motomura Т., Aramaki H., Matsuda T., Yamashita M., Ito Y., Matsuzaki Y., Yamataka K., Ikeda S., et al. // J. Med. Chem. 2009. V. 52. № 15. P. 4869-4882.
  74. Correll Т., Klibanov O.M. // Pharmacotherapy. 2008. V. 28. № 1. P. 90-101.
  75. DeJesus E., Berger D., Markowitz M., Cohen C., Hawkins Т., Ruane P., Elion R., Farthing C., Zhong L., Cheng A.K., et al. // J. Acquir. Immune. Defic. Syndr. 2006. V. 43. № 1. P. 1-5.
  76. Zolopa A.R., Berger D.S., Lampiris H., Zhong L., Chuck S.L., Enejosa J.V., Kearney B.P., Cheng A.K. // J. Infect. Dis. 2010. V. 201. № 6. P. 814-822.
  77. Cohen C., Elion R., Ruane P., Shamblaw D., DeJesus E., Rashbaum B., Chuck S.L., Yale K., Liu H.C., Warren D.R., et al. // AIDS. 2011. V. 25. № 6. P. F7-F12.
  78. McColl D.J., Fransen S., Gupta S., Parkin N., Margot N., Chuck S., Cheng A.K., Miller M.D. // Antivir. Ther. 2007. V. 12. P. S11-S111.
  79. Ceccherini-Silberstein F., Malet I., D’Arrigo R., Antinori A., Marcelin A.G., Perno C.F. // AIDS Rev. 2009. V. 11. № 1. P. 17-29.
  80. Goethals O., Clayton R., van Ginderen M., Vereycken I., Wagemans E., Geluykens P., Dockx K., Strijbos R., Smits V., Vos A., et al. // J. Virol. 2008. V. 82. № 21. P. 10366-10374.
  81. Langley D.R., Samanta H.K., Lin Z., Walker M.A., Krystal M.R., Dicker I.B. // Biochemistry. 2008. V. 47. P. 13481-13488.
  82. Marinello J., Marchand C., Mott B.T., Bain A., Thomas C.J., Pommier Y. // Biochemistry. 2008. V. 47. № 36. P. 9345-9354.
  83. Kobayashi M., Nakahara K., Seki Т., Miki S., Kawauchi S., Suyama A., Wakasa-Morimoto C., Kodama M., Endoh Т., Oosugi E., et al. // Antiviral Res. 2008. V. 80. № 2. P. 213-222.
  84. Nakahara K., Wakasa-Morimoto C., Kobayashi M., Miki S., Noshi Т., Seki Т., Kanamori-Koyama M., Kawauchi S., Suyama A., Fujishita Т., et al. // Antiviral Res. 2009. V. 81. № 2. P. 141-146.
  85. an Baelen K., van Eygen V., Rondelez E., Stuyver L.J. // AIDS. 2008. V. 22. P. 1877-1880.
  86. Bar-Magen Т., Donahue D.A., McDonough E.I. // AIDS. 2010. V. 24. № 14. P. 2171-2179.
  87. Maiga A.I., Malet I., Soulie C., Derache A., Koita V., Amellal B., Tchertanov L., Delelis O., Morand-Joubert L., Mouscadet J.-F., et al. // Antivir. Ther. 2009. V. 14. P. 123-129.
  88. Sichtig N., Sierra S., Kaiser R., Daumer M., Reuter S., Schulter E., Altmann A., Fatkenheuer G., Dittmer U., Pfister H., et al. // J. Antimicrob. Chemother. 2009. V. 64. P. 25-32.
  89. Mekouar K., Mouscadet J.-F., Desmaёle D., Subra F., Leh H., Savoure D., Auclair C., d’Angelo J. // J. Med. Chem. 1998. V. 41. P. 2846-2857.
  90. Ouali M., Laboulais C., Leh H., Gill D., Desmaele D., Mekouar K., Zouhiri F., d’Angelo J., Auclair C., Mouscadet J.-F., et al. // J. Med. Chem. 2000. V. 43. № 10. P. 1949-1957.
  91. Zouhiri F., Mouscadet J.-F., Khalid Mekouar K., Desmaёle D., Savouré D., Leh H., Subra F., Le Bret M., Auclair C., d’Angelo J. // J. Med. Chem. 2000. V. 43. P. 1533-1540.
  92. Deprez E., Barbe S., Kolaski M., Leh H., Zouhiri F., Auclair C., Brochon J.-C., Le Bret M., Mouscadet J.-F. // Mol. Pharmacol. 2004. V. 65. № 1. P. 85-98.
  93. Pannecouque C., Pluymers W., van Maele B., Tetz V., Cherepanov P., De Clercq E., Witvrouw M., Debyser Z. // Curr. Biol. 2002. V. 12. № 14. P. 1169-1177.
  94. Hombrouck A., Hantson A., van Remoortel B., Michiels M., Vercammen J., Rhodes D., Tetz V., Engelborghs Y., Christ F., Debyser Z., et al. // J. Antimicrob. Chemother. 2007. V. 59. № 6. P. 1084-1095.
  95. Al-Mawsawi L.Q., Neamati N. // Trends Pharmacol. Sci. 2007. V. 28. № 10. P. 526-535.
  96. Mazumder A., Wang S., Neamati N., Nicklaus M., Sunder S., Chen J., Milne G.W.A., Rice W.G., Burke T.R. Jr., Pommier Y. // J. Med. Chem. 1996. V. 39. P. 2472-2481.
  97. Al-Mawsawi L.Q., Fikkert V., Dayam R., Witvrouw M., Burke T.R. Jr., Borchers C.H., Neamati N. // Proc. Natl. Acad. Sci. USA. 2006. V. 103. № 26. P. 10080-10085.
  98. De Luca L., Barreca M.L., Ferro S., Christ F., Iraci N., Gitto R., Monforte A.M., Debyser Z., Chimirri A. // Chem. Med. Chem. 2009. V. 4. № 8. P. 1311-1316.
  99. Al-Mawsawi L.Q., Christ F., Dayam R., Debyser Z., Neamati N. // FEBS Lett. 2008. V. 582. № 10. P. 1425-1430.

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