Novel therapeutic strategies targeting HIV integrase

BMC Medicine

Volumn 10, Issue , 2012, Pages

  Quashie, Peter K ^a,b   Sloan, Richard D ^a   Wainberg, Mark A ^a,b  

^a MCGILL UNIVERSITY   (Canada)

^b MCGILL UNIVERSITY   (Canada)

Author keywords

Crystal structure; Dolutegravir; HIV integrase; Mutations; New drugs; Raltegravir; Resistance

Indexed keywords

ATAZANAVIR; BI C; DOLUTEGRAVIR; EFAVIRENZ; ELVITEGRAVIR; INTEGRASE; L31988; L870812; MK 0536; MK 2048; NEVIRAPINE; RALTEGRAVIR; RIFAMPICIN; UNCLASSIFIED DRUG; INTEGRASE INHIBITOR; INTEGRATION HOST FACTOR;

ANTIVIRAL ACTIVITY; CELL CULTURE; CRYSTAL STRUCTURE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG HALF LIFE; DRUG METABOLISM; DRUG STRUCTURE; GENE MUTATION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IC 50; IN VITRO STUDY; REVIEW; TREATMENT FAILURE; VIREMIA; VIRUS DNA CELL DNA INTERACTION; VIRUS REPLICATION; CHEMISTRY; DRUG EFFECT; HUMAN IMMUNODEFICIENCY VIRUS; METABOLISM; MOLECULARLY TARGETED THERAPY; QUANTITATIVE STRUCTURE ACTIVITY RELATION;

HIV; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HUMANS; INTEGRATION HOST FACTORS; MOLECULAR TARGETED THERAPY; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84859641222     PISSN: None     EISSN: 17417015     Source Type: Journal    
DOI: 10.1186/1741-7015-10-34     Document Type: Review

References (123)

1. Coffin JM, Hughes SH, Varmus HE. Retroviruses. 1997, Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.
2. Gupta SP, Nagappa AN. Design and development of integrase inhibitors as anti-HIV agents. Curr Med Chem 2003, 10(18):1779-1794. 10.2174/0929867033456972, 12871104.
3. 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(21):5103-5111. 10.1046/j.1432-1033.2002.03216.x, 12392542.
4. Maurin C, Bailly F, Cotelle P. Structure-activity relationships of HIV-1 integrase inhibitors--enzyme-ligand interactions. Curr Med Chem 2003, 10(18):1795-1810. 10.2174/0929867033456981, 12871105.
5. Singh SB, Jayasuriya H, Salituro GM, Zink DL, Shafiee A, Heimbuch B, Silverman KC, Lingham RB, 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(7):874-882. 10.1021/np000632z, 11473415.
6. Jing N, Xu X. Rational drug design of DNA oligonucleotides as HIV inhibitors. Curr Drug Targets Infect Disord 2001, 1(2):79-90. 10.2174/1568005013343173, 12455406.
7. Brigo A, Mustata GI, Briggs JM, Moro S. Discovery of HIV-1 integrase inhibitors through a novel combination of ligand and structure-based drug design. Med Chem 2005, 1(3):263-275. 10.2174/1573406053765440, 16787322.
8. de Soultrait VR, Desjobert C, Tarrago-Litvak L. Peptides as new inhibitors of HIV-1 reverse transcriptase and integrase. Curr Med Chem 2003, 10(18):1765-1778. 10.2174/0929867033457007, 12871103.
9. Hazuda DJ, Felock P, Witmer M, Wolfe A, Stillmock K, Grobler JA, Espeseth A, Gabryelski L, Schleif W, Blau C, Miller MD. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000, 287(5453):646-650. 10.1126/science.287.5453.646, 10649997.
10. Reinke R, Lee DJ, Robinson WE. Inhibition of human immunodeficiency virus type 1 isolates by the integrase inhibitor L-731,988, a diketo Acid. Antimicrob Agents Chemother 2002, 46(10):3301-3303. 10.1128/AAC.46.10.3301-3303.2002, 128787, 12234866.
11. Hazuda D, Iwamoto M, Wenning L. Emerging pharmacology: inhibitors of human immunodeficiency virus integration. Annu Rev Pharmacol Toxicol 2009, 49:377-394. 10.1146/annurev.pharmtox.011008.145553, 18928385.
12. Marchand C, Zhang X, Pais GC, Cowansage K, Neamati N, Burke TR, Pommier Y. Structural determinants for HIV-1 integrase inhibition by beta-diketo acids. J Biol Chem 2002, 277(15):12596-12603. 10.1074/jbc.M110758200, 11805103.
13. Goldgur Y, Craigie R, Cohen GH, Fujiwara T, Yoshinaga T, Fujishita T, Sugimoto H, Endo T, Murai H, Davies DR. Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: a platform for antiviral drug design. Proc Natl Acad Sci USA 1999, 96(23):13040-13043. 10.1073/pnas.96.23.13040, 23896, 10557269.
14. Derwent Abstract No. 1999-580735/49, "New indole derivatives are integrase inhibitors useful as antiviral and anit-HIV agents". abstract of WO 99/50245 Shionogi & Co, Ltd 1999,
15. Rosemond MJ, St John-Williams L, Yamaguchi T, Fujishita T, Walsh JS. Enzymology of a carbonyl reduction clearance pathway for the HIV integrase inhibitor, S-1360: role of human liver cytosolic aldo-keto reductases. Chem Biol Interact 2004, 147(2):129-139. 10.1016/j.cbi.2003.12.001, 15013815.
16. FDA notifications. FDA approves raltegravir for HIV-1 treatment-naive patients. AIDS Alert 2009, 24(9):106-107.
17. Steigbigel RT, Cooper DA, Teppler H, Eron JJ, Gatell JM, Kumar PN, Rockstroh JK, Schechter M, Katlama C, Markowitz M, Yeni P, Loutfy MR, Lazzarin A, Lennox JL, Clotet B, Zhao J, Wan H, Rhodes RR, Strohmaier KM, Barnard RJ, Isaacs RD, Nguyen BY, . BENCHMRK Study Teamsa Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clin Infect Dis 2010, 50(4):605-612. 10.1086/650002, 20085491, BENCHMRK Study Teamsa.
18. Donahue DA, Sloan RD, Kuhl BD, Bar-Magen T, Schader SM, Wainberg MA. Stage-dependent inhibition of HIV-1 replication by antiretroviral drugs in cell culture. Antimicrob Agents Chemother 2010, 54(3):1047-1054. 10.1128/AAC.01537-09, 2826010, 20038621.
19. Grinsztejn B, Nguyen BY, Katlama C, Gatell JM, Lazzarin A, Vittecoq D, Gonzalez CJ, Chen J, Harvey CM, Isaacs RD, . Protocol 005 Team 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(9569):1261-1269. 10.1016/S0140-6736(07)60597-2, 17434401, Protocol 005 Team.
20. Wenning LA, Hanley WD, Brainard DM, Petry AS, Ghosh K, Jin B, Mangin E, Marbury TC, Berg JK, Chodakewitz JA, Stone JA, Gottesdiener KM, Wagner JA, Iwamoto M. Effect of rifampin, a potent inducer of drug-metabolizing enzymes, on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother 53:2852-2856.
21. Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, Prada G, Morales-Ramirez JO, Crumpacker CS, Isaacs RD, Gilde LR, Wan H, Miller MD, Wenning LA, Teppler H, . Protocol 004 Part II Study Team 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 Acquir Immune Defic Syndr 2007, 46(2):125-133. 10.1097/QAI.0b013e318157131c, 17721395, Protocol 004 Part II Study Team.
22. Eron JJ, Rockstroh JK, Reynes J, Andrade-Villanueva J, Ramalho-Madruga JV, Bekker LG, Young B, Katlama C, Gatell-Artigas JM, Arribas JR, Nelson M, Campbell H, Zhao J, Rodgers AJ, Rizk ML, Wenning L, Miller MD, Hazuda D, DiNubile MJ, Leavitt R, Isaacs R, Robertson MN, Sklar P, Nguyen BY, . QDMRK Investigators Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial. Lancet Infect Dis 2011, 11(12):907-915. 10.1016/S1473-3099(11)70196-7, 21933752, QDMRK Investigators.
23. Vispo E, Barreiro P, Maida I, Mena A, Blanco F, Rodríguez-Novoa S, Morello J, Jimenez-Nacher I, Gonzalez-Lahoz J, Soriano V. Simplification from protease inhibitors to once- or twice-daily raltegravir: the ODIS trial. HIV Clin Trials 2010, 11(4):197-204. 10.1310/hct1104-197, 20974575.
24. Lanzafame M, Hill A, Lattuada E, Calcagno A, Bonora S. Raltegravir: is a 400 mg once-daily dose enough?. J Antimicrob Chemother 2010, 65(3):595-597. 10.1093/jac/dkp488, 20071368.
25. Malet I, Delelis O, Valantin MA, Montes B, Soulie C, Wirden M, Tchertanov L, Peytavin G, Reynes J, Mouscadet JF, Katlama C, Calvez V, Marcelin AG. Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob Agents Chemother 2008, 52(4):1351-1358. 10.1128/AAC.01228-07, 2292515, 18227187.
26. Garrido C, de Mendoza C, Soriano V. [Resistance to integrase inhibitors]. Enferm Infecc Microbiol Clin 2008, 26(Suppl 12):40-46.
27. Bar-Magen T, Donahue DA, McDonough EI, Kuhl BD, Faltenbacher VH, Xu H, Michaud V, Sloan RD, Wainberg MA. HIV-1 subtype B and C integrase enzymes exhibit differential patterns of resistance to integrase inhibitors in biochemical assays. AIDS 2010, 24(14):2171-2179. 10.1097/QAD.0b013e32833cf265, 20647908.
28. Delelis O, Malet I, Na L, Tchertanov L, Calvez V, Marcelin AG, Subra F, Deprez E, Mouscadet JF. The G140S mutation in HIV integrases from raltegravir-resistant patients rescues catalytic defect due to the resistance Q148H mutation. Nucleic Acids Res 2009, 37(4):1193-1201. 2651800, 19129221.
29. Johnson VA, Brun-Vézinet F, Clotet B, Günthard HF, Kuritzkes DR, Pillay D, Schapiro JM, Richman DD. Update of the drug resistance mutations in HIV-1: December 2010. Top HIV Med 2010, 18(5):156-163.
30. Hu Z, Kuritzkes DR. Effect of raltegravir resistance mutations in HIV-1 integrase on viral fitness. J Acquir Immune Defic Syndr 2010, 55(2):148-155. 10.1097/QAI.0b013e3181e9a87a, 2943977, 20634701.
31. Canducci F, Barda B, Ceresola E, Spagnuolo V, Sampaolo M, Boeri E, Nozza S, Cossarin F, Galli A, Gianotti N, Castagna A, Lazzarin A, Clementi M. Evolution patterns of raltegravir-resistant mutations after integrase inhibitor interruption. Clin Microbiol Infect 2011, 17(6):928-934. 10.1111/j.1469-0691.2010.03375.x, 20854427.
32. Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P, Lazzarin A, Clotet B, Kumar PN, Eron JE, Schechter M, Markowitz M, Loutfy MR, Lennox JL, Zhao J, Chen J, Ryan DM, Rhodes RR, Killar JA, Gilde LR, Strohmaier KM, Meibohm AR, Miller MD, Hazuda DJ, Nessly ML, DiNubile MJ, Isaacs RD, Teppler H, Nguyen BY, . BENCHMRK Study Teams Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008, 359(4):355-365. 10.1056/NEJMoa0708978, 18650513, BENCHMRK Study Teams.
33. Blanco JL, Varghese V, Rhee SY, Gatell JM, Shafer RW. HIV-1 integrase inhibitor resistance and its clinical implications. J Infect Dis 2011, 203(9):1204-1214. 10.1093/infdis/jir025, 3069732, 21459813.
34. Eron JJ, Young B, Cooper DA, Youle M, Dejesus E, Andrade-Villanueva J, Workman C, Zajdenverg R, Fätkenheuer G, Berger DS, Kumar PN, Rodgers AJ, Shaughnessy MA, Walker ML, Barnard RJ, Miller MD, Dinubile MJ, Nguyen BY, Leavitt R, Xu X, Sklar P, . SWITCHMRK 1 and 2 investigators Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet 2010, 375(9712):396-407. 10.1016/S0140-6736(09)62041-9, 20074791, SWITCHMRK 1 and 2 investigators.
35. Klibanov OM. Elvitegravir, an oral HIV integrase inhibitor, for the potential treatment of HIV infection. Curr Opin Investig Drugs 2009, 10(2):190-200.
36. 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(5):1506-1508. 10.1021/jm0600139, 16509568.
37. DeJesus E. Antiretroviral Agents in Development. , http://www.thebody.com/content/art1352.html
38. Annonymous Single-tablet quad regimen achieves high rate of virologic suppression. AIDS Patient Care STDS 2010, 24(3):197. Annonymous.
39. Ramanathan S, Mathias AA, German P, Kearney BP. Clinical pharmacokinetic and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin Pharmacokinet 2011, 50(4):229-244. 10.2165/11584570-000000000-00000, 21348537.
40. Mathias AA, West S, Hui J, Kearney BP. Dose-response of ritonavir on hepatic CYP3A activity and elvitegravir oral exposure. Clin Pharmacol Ther 2009, 85(1):64-70. 10.1038/clpt.2008.168, 18815591.
41. DeJesus E, Berger D, Markowitz M, Cohen C, Hawkins T, Ruane P, Elion R, Farthing C, Zhong L, Cheng AK, . The 183-Study Team Antiviral Activity, Pharmacokinetics, and Dose Response of the HIV-1 Integrase Inhibitor GS-9137 (JTK-303) in Treatment-Naive and Treatment-Experienced Patients. JAIDS 2006, 43(1):1-5. 10.1097/01.qai.0000233308.82860.2f, 16936557, The 183-Study Team.
42. Highleyman L. Elvitegravir "Quad" Single-tablet Regimen Shows Continued HIV Suppression at 48 Weeks. , http://www.hivandhepatitis.com/2010_conference/icaac/docs/0914_a.html
43. Zolopa AR, Berger DS, Lampiris H, Zhong L, Chuck SL, Enejosa JV, Kearney BP, Cheng AK. 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 2010, 201(6):814-822. 10.1086/650698, 20146631.
44. 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(21):10366-10374. 10.1128/JVI.00470-08, 2573211, 18715920.
45. Taiwo B, Zheng L, Gallien S, Matining RM, Kuritzkes DR, Wilson CC, Berzins BI, Acosta EP, Bastow B, Kim PS, Eron JJ, . ACTG A5262 Team Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naïve HIV-1-infected patients (ACTG A5262). AIDS 2011, 25(17):2113-2122. 10.1097/QAD.0b013e32834bbaa9, 21857490, ACTG A5262 Team.
46. 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(9):1175-1178. 10.1097/QAD.0b013e3283473599, 21505303.
47. 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(2):764-774. 10.1128/JVI.01534-07, 2224569, 17977962.
48. Dicker IB, Terry B, Lin Z, Li Z, Bollini S, Samanta HK, Gali V, Walker MA, Krystal MR. Biochemical analysis of HIV-1 integrase variants resistant to strand transfer inhibitors. J Biol Chem 2008, 283(35):23599-23609. 10.1074/jbc.M804213200, 3259799, 18577511.
49. McColl DJ, Chen X. Strand transfer inhibitors of HIV-1 integrase: bringing in a new era of antiretroviral therapy. Antivir Res 2010, 85:101-18. 10.1016/j.antiviral.2009.11.004, 19925830.
50. Canducci F, Sampaolo M, Marinozzi MC, Boeri E, Spagnuolo V, Galli A, Castagna A, Lazzarin A, Clementi M, Gianotti N. Dynamic patterns of human immunodeficiency virus type 1 integrase gene evolution in patients failing raltegravir-based salvage therapies. AIDS 2009, 23(4):455-460. 10.1097/QAD.0b013e328323da60, 19165083.
51. Al-Mawsawi LQ, Al-Safi RI, Neamati N. Anti-infectives: clinical progress of HIV-1 integrase inhibitors. Expert Opin Emerg Drugs 2008, 13(2):213-225. 10.1517/14728214.13.2.213, 18537517.
52. Vacca J, Wai J, Fisher T, Embrey M, Hazuda D, Miller M, Felock P, Witmer M, Gabryelski L, Lyle T. Discovery of MK-2048 - subtle changes confer unique resistance properties to a series of tricyclic hydroxypyrrole integrase strand transfer inhibitor. , http://www.ias2007.org/pag/Abstracts.aspx?AID=3234
53. Van Wesenbeeck L, Rondelez E, Feyaerts M, Verheyen A, Van der Borght K, Smits V, Cleybergh C, De Wolf H, Van Baelen K, Stuyver LJ. 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(1):321-325. 10.1128/AAC.01733-09, 3019647, 20956600.
54. Pandey KK, Bera S, Vora AC, Grandgenett DP. Physical trapping of HIV-1 synaptic complex by different structural classes of integrase strand transfer inhibitors. Biochemistry 2010, 49(38):8376-8387. 10.1021/bi100514s, 2965028, 20799722.
55. Goethals O, van Ginderen M, Vos A, Cummings MD, van Der Borght K, van Wesenbeeck L, Feyaerts M, Verheyen A, Smits V, van Loock M, Hertogs K, Schols D, Clayton RF. 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(2):167-176. 10.1016/j.antiviral.2011.05.011, 21669228.
56. Bar-Magen T, Sloan RD, Donahue DA, Kuhl BD, Zabeida A, Xu H, Oliveira M, Hazuda DJ, Wainberg MA. Identification of novel mutations responsible for resistance to MK-2048, a second-generation HIV-1 integrase inhibitor. J Virol 2010, 84(18):9210-9216. 10.1128/JVI.01164-10, 2937597, 20610719.
57. Raltegravir shows promise as a PREP drug. , http://www.aidsmap.com/Raltegravir-shows-potential-for-use-as-PrEP-drug/page/1434320/
58. Seegulam ME, Ratner L. Integrase inhibitors effective against human T-cell leukemia virus type 1. Antimicrob Agents Chemother 2011, 55(5):2011-2017. 10.1128/AAC.01413-10, 3088187, 21343468.
59. Eron J, Livrozet JM, Morlat P, Lazzarin A, Katlama C, Hawkins T, Fujiwara T, Cuffe R, Vavro C, Santiago J, Ait-Khaled M, Min S, Yeo JM. 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.
60. Yoshinaga Y, Kanamori-Koyama M, Seki T, Ishida K, Akihisa E, Kobayashi M, Sato A, Fujiwara Shionogi T. Strong inhibition of wild-type and integrase inhibitor (INI)-resistant HIV integrase (IN) strand transfer reaction by the novel INI S/GSK1349572. International HIV & Hepatitis Virus Drug Resistance Workshop. vol. Poster. Dubrovnik, Croatia; 2010 2010, Levin: Conference reports for NATAP., http://www.natap.org/2010/ResisWksp/ResisWksp_31.htm
61. Bar-Magen T, Sloan RD, Faltenbacher VH, Donahue DA, Kuhl BD, Oliveira M, Xu H, Wainberg MA. Comparative biochemical analysis of HIV-1 subtype B and C integrase enzymes. Retrovirology 2009, 6:103. 10.1186/1742-4690-6-103, 2779801, 19906306.
62. Sloan RD, Wainberg MA. The role of unintegrated DNA in HIV infection. Retrovirology 2011, 8:52. 10.1186/1742-4690-8-52, 3148978, 21722380.
63. Seki TKM, Wakasa-Morimoto C, Yoshinaga T, Sato A, Fujiwara T, Underwood M, Garvey EP, Johns BA. S/GSK1349572 Is a Potent Next Generation HIV Integrase Inhibitor and Demonstrates a Superior Resistance Profile Substantiated with 60 Integrase Mutant Molecular Clones. , http://www.retroconference.org/2010/Abstracts/38374.htm
64. 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. 5th International AIDS Society's Conference on HIV Pathogenesis, Cape Town, South Africa 2009 2009, Levin: Conference Reports for NATAP, 2880256, 20519026., http://www.natap.org/2009/IAS/IAS_06.htm
65. Kobayashi M, Yoshinaga T, Seki T, Wakasa-Morimoto C, Brown KW, Ferris R, Foster SA, Hazen RJ, Miki S, Suyama-Kagitani A, Kawauchi-Miki S, Taishi T, Kawasuji T, Johns BA, Underwood MR, Garvey EP, Sato A, Fujiwara T. In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother 2011, 55(2):813-821. 10.1128/AAC.01209-10, 3028777, 21115794.
66. Min S, Song I, Borland J, Chen S, Lou Y, Fujiwara T, Piscitelli SC. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother 2010, 54(1):254-258. 10.1128/AAC.00842-09, 2798521, 19884365.
67. Lalezari J, Sloan L, DeJesus E, Hawkins T, McCurdy L, Song I, Borland J, Stroder R, Chen S, Lou Y, Underwood M, Fujiwara T, Piscitelli S, Min S. Potent antiviral activity of S/GSK1349572, a next generation ontegrase onhibitor (INI), in INI-naïve HIV-1-infected patients: ING111521 Protocol. , http://www.ias2009.org/pag/Abstracts.aspx?AID=2120
68. 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(14):1737-1745. 10.1097/QAD.0b013e32834a1dd9, 21716073.
69. Rockstroh J, Felizarta F, Maggiolo F, Pulido F, Stellbrink HJ, Tsybakova O, Yeni P, Almond S, Brothers C, Song I, Min S. Once-daily S/GSK1349572 combination therapy in antiretroviral-naïve adults: rapid and potent 24-week antiviral responses in SPRING-1 (ING112276). J Int AIDS Soc 2010, 13(Suppl 4):O50.
70. Mascolini M. Gilead Integrase Inhibitor Outdoes New PIs in Salvage Therapy. , http://www.natap.org/2007/CROI/croi_29.htm
71. Quashie PK, Mesplède T, Han YS, Oliveira M, Singhroy DN, Fujiwara T, Underwood MR, Wainberg MA. 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(5):2696-2705. 10.1128/JVI.06591-11, 22205735.
72. Hightower KE, Wang R, Deanda F, Johns BA, Weaver K, Shen Y, Tomberlin GH, Carter HL, Broderick T, Sigethy S, Seki T, Kobayashi M, Underwood MR. 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(10):4552-4559. 10.1128/AAC.00157-11, 3187001, 21807982.
73. Mascolini M. Merck Offers Unique Perspective on Second-Generation Integrase Inhibitor. , http://www.natap.org/2009/PK/PK_10.htm
74. Hare S, Smith SJ, Métifiot M, Jaxa-Chamiec A, Pommier Y, Hughes SH, Cherepanov P. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol 2011, 80(4):565-572. 10.1124/mol.111.073189, 3187526, 21719464.
75. Garrido C, Soriano V, Geretti AM, Zahonero N, Garcia S, Booth C, Gutierrez F, Viciana I, de Mendoza C. Resistance associated mutations to dolutegravir (S/GSK1349572) in HIV-infected patients - impact of HIV subtypes and prior raltegravir experience. Antiviral Res 2011, 90(3):164-167. 10.1016/j.antiviral.2011.03.178, 21439330.
76. Malet I, Wirden M, Fourati S, Armenia D, Masquelier B, Fabeni L, Sayon S, Katlama C, Perno CF, Calvez V, Marcelin AG, Ceccherini-Silberstein F. Prevalence of resistance mutations related to integrase inhibitor S/GSK1349572 in HIV-1 subtype B raltegravir-naive and -treated patients. J Antimicrob Chemother 2011, 66(7):1481-1483. 10.1093/jac/dkr152, 21474479.
77. O' Neal R. Dolutegravir: a new integrase inhibitor in development. , http://www.sfaf.org/hiv-info/hot-topics/beta/2011-beta-winterspring-drug-watch.pdf
78. 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
79. Jenkins TM, Hickman AB, Dyda F, Ghirlando R, Davies DR, Craigie R. Catalytic domain of human immunodeficiency virus type 1 integrase: identification of a soluble mutant by systematic replacement of hydrophobic residues. Proc Natl Acad Sci USA 1995, 92(13):6057-6061. 10.1073/pnas.92.13.6057, 41641, 7597080.
80. Jenkins TM, Engelman A, Ghirlando R, Craigie R. A soluble active mutant of HIV-1 integrase: involvement of both the core and carboxyl-terminal domains in multimerization. J Biol Chem 1996, 271(13):7712-7718. 10.1074/jbc.271.13.7712, 8631811.
81. Dyda F, Hickman AB, Jenkins TM, Engelman A, Craigie R, Davies DR. Crystal structure of the catalytic domain of HIV-1 integrase: similarity to other polynucleotidyl transferases. Science 1994, 266(5193):1981-1986. 10.1126/science.7801124, 7801124.
82. Hare S, Di Nunzio F, Labeja A, Wang J, Engelman A, Cherepanov P. Structural basis for functional tetramerization of lentiviral integrase. PLoS Pathog 2009, 5(7):e1000515. 10.1371/journal.ppat.1000515, 2705190, 19609359.
83. Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 2010, 464(7286):232-236. 10.1038/nature08784, 2837123, 20118915.
84. Hare S, Vos AM, Clayton RF, Thuring JW, Cummings MD, Cherepanov P. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc Natl Acad Sci USA 2010, 107(46):20057-20062. 10.1073/pnas.1010246107, 2993412, 21030679.
85. Krishnan L, Li X, Naraharisetty HL, Hare S, Cherepanov P, Engelman A. Structure-based modeling of the functional HIV-1 intasome and its inhibition. Proc Natl Acad Sci USA 2010, 107(36):15910-15915. 10.1073/pnas.1002346107, 2936642, 20733078.
86. Maertens GN, Hare S, Cherepanov P. The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature 2010, 468(7321):326-329. 10.1038/nature09517, 2999894, 21068843.
87. Kessl JJ, Li M, Ignatov M, Shkriabai N, Eidahl JO, 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(20):9009-9022. 10.1093/nar/gkr581, 3203615, 21771857.
88. Li X, Krishnan L, Cherepanov P, Engelman A. Structural biology of retroviral DNA integration. Virology 2011, 411(2):194-205. 10.1016/j.virol.2010.12.008, 21216426.
89. Cherepanov P, Maertens GN, Hare S. Structural insights into the retroviral DNA integration apparatus. Curr Opin Struct Biol 2011, 21(2):249-256. 10.1016/j.sbi.2010.12.005, 21277766.
90. Hall LH. A structure-information approach to the prediction of biological activities and properties. Chem Biodivers 2004, 1(1):183-201. 10.1002/cbdv.200490010, 17191786.
91. Liu Q, Zhou H, Liu L, Chen X, Zhu R, Cao Z. Multi-target QSAR modelling in the analysis and design of HIV-HCV co-inhibitors: an in-silico study. BMC Bioinformatics 2011, 12:294. 10.1186/1471-2105-12-294, 3167801, 21774796.
92. Johnson BC, Métifiot M, Pommier Y, Hughes SH. Molecular dynamics approaches estimate the binding energy of HIV-1 integrase inhibitors and correlate with in vitro activity. Antimicrob Agents Chemother 2012, 56(1):411-419. 10.1128/AAC.05292-11, 22037850.
93. Liao C, Nicklaus MC. Computer tools in the discovery of HIV-1 integrase inhibitors. Future Med Chem 2010, 2(7):1123-1140. 10.4155/fmc.10.193, 21426160.
94. Egbertson MS, Wai JS, Cameron M, Hoerrner RS. Discovery of MK-0536: A potential second-generation HIV-1 integrase strand transfer inhibitor with a high genetic barrier to mutation. Antiviral Drugs: From Basic Discovery through Clinical Trials 2011, Hoboken, NJ, USA: John Wiley & Sons, Inc, Kazmierski WM.
95. Métifiot M, Johnson B, Smith S, Zhao XZ, Marchand C, Burke T, Hughes S, Pommier Y. MK-0536 inhibits HIV-1 integrases resistant to raltegravir. Antimicrob Agents Chemother 2011, 55(11):5127-5133. 10.1128/AAC.05288-11, 21876054.
96. He Y, Wang Z, Wu B, IRM LLC. Terephthalamate compounds and compositions, and their use as HIV integrase inhibitors. , http://www.faqs.org/patents/app/20100016379
97. Pace P, Di Francesco ME, Gardelli C, Harper S, Muraglia E, Nizi E, Orvieto F, Petrocchi A, Poma M, Rowley M, Scarpelli R, Laufer R, Gonzalez Paz O, Monteagudo E, Bonelli F, Hazuda D, Stillmock KA, Summa V. Dihydroxypyrimidine-4-carboxamides as novel potent and selective HIV integrase inhibitors. J Med Chem 2007, 50(9):2225-2239. 10.1021/jm070027u, 17428043.
98. Muraglia E, Kinzel O, Gardelli C, Crescenzi B, Donghi M, Ferrara M, Nizi E, Orvieto F, Pescatore G, Laufer R, Gonzalez-Paz O, Di Marco A, Fiore F, Monteagudo E, Fonsi M, Felock PJ, Rowley M, Summa V. Design and synthesis of bicyclic pyrimidinones as potent and orally bioavailable HIV-1 integrase inhibitors. J Med Chem 2008, 51(4):861-874. 10.1021/jm701164t, 18217703.
99. Telvekar VN, Patel KN. Pharmacophore development and docking studies of the hiv-1 integrase inhibitors derived from N-methylpyrimidones, dihydroxypyrimidines, and bicyclic pyrimidinones. Chem Biol Drug Des 2011, 78(1):150-160. 10.1111/j.1747-0285.2011.01130.x, 21518263.
100. Johnson TW, Tanis SP, Butler SL, Dalvie D, Delisle DM, Dress KR, Flahive EJ, Hu Q, Kuehler JE, Kuki A, Liu W, McClellan GA, Peng Q, Plewe MB, Richardson PF, Smith GL, Solowiej J, Tran KT, Wang H, Yu X, Zhang J, Zhu H. Design and synthesis of novel N-hydroxy-dihydronaphthyridinones as potent and orally bioavailable HIV-1 integrase inhibitors. J Med Chem 2011, 54(9):3393-3417. 10.1021/jm200208d, 21446745.
101. Wai JS, Kim B, Fisher TE, Zhuang L, Embrey MW, Williams PD, Staas DD, Culberson C, Lyle TA, Vacca JP, Hazuda DJ, Felock PJ, Schleif WA, Gabryelski LJ, Jin L, Chen IW, Ellis JD, Mallai R, Young SD. Dihydroxypyridopyrazine-1,6-dione HIV-1 integrase inhibitors. Bioorg Med Chem Lett 2007, 17(20):5595-5599. 10.1016/j.bmcl.2007.07.092, 17822898.
102. Toropova AP, Toropov AA, Benfenati E, Gini G. Simplified molecular input-line entry system and International Chemical Identifier in the QSAR analysis of styrylquinoline derivatives as HIV-1 integrase inhibitors. Chem Biol Drug Des 2011, 77(5):343-360. 10.1111/j.1747-0285.2011.01109.x, 21352501.
103. Nagasawa JY, Song J, Chen H, Kim HW, Blazel J, Ouk S, Groschel B, Borges V, Ong V, Yeh LT, Girardet JL, Vernier JM, Raney AK, Pinkerton AB. 6-Benzylamino 4-oxo-1,4-dihydro-1,8-naphthyridines and 4-oxo-1,4-dihydroquinolines as HIV integrase inhibitors. Bioorg Med Chem Lett 2011, 21(2):760-763. 10.1016/j.bmcl.2010.11.108, 21185178.
104. Van Maele B, Busschots K, Vandekerckhove L, Christ F, Debyser Z. Cellular co-factors of HIV-1 integration. Trends Biochem Sci 2006, 31(2):98-105. 10.1016/j.tibs.2005.12.002, 16403635.
105. Sloan RD, Wainberg MA. The role of unintegrated DNA in HIV infection. Retrovirology 2011, 8:52. 10.1186/1742-4690-8-52, 3148978, 21722380.
106. Zamborlini A, Coiffic A, Beauclair G, Delelis O, Paris J, Koh Y, Magne F, Giron ML, Tobaly-Tapiero J, Deprez E, Emiliani S, Engelman A, de Thé H, Saïb A. Impairment of human immunodeficiency virus type-1 integrase SUMOylation correlates with an early replication defect. J Biol Chem 2011, 286(23):21013-21022. 10.1074/jbc.M110.189274, 21454548.
107. Terreni M, Valentini P, Liverani V, Gutierrez MI, 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. 10.1186/1742-4690-7-18, 2848186, 20226045.
108. Buzon MJ, Seiss K, Weiss R, Brass AL, Rosenberg ES, Pereyra F, Yu XG, Lichterfeld M. Inhibition of HIV-1 integration in ex vivo-infected CD4 T cells from elite controllers. J Virol 2011, 85(18):9646-9650. 10.1128/JVI.05327-11, 3165766, 21734042.
109. Christ F, Voet A, Marchand A, Nicolet S, Desimmie BA, Marchand D, Bardiot D, van der Veken NJ, van Remoortel B, Strelkov SV, 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(6):442-448.
110. McNeely M, Hendrix J, Busschots K, Boons E, Deleersnijder A, Gerard M, Christ F, Debyser Z. In vitro DNA tethering of HIV-1 integrase by the transcriptional coactivator LEDGF/p75. J Mol Biol 2011, 410(5):811-830. 10.1016/j.jmb.2011.03.073, 21763490.
111. De Luca L, Ferro S, Gitto R, Barreca ML, 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(21):7515-7521. 10.1016/j.bmc.2010.08.051, 20850978.
112. Madlala P, Gijsbers R, Christ F, Hombrouck A, Werner L, Mlisana K, An P, Abdool Karim SS, Winkler CA, Debyser Z, Ndung'u T. Association of polymorphisms in the LEDGF/p75 gene (PSIP1) with susceptibility to HIV-1 infection and disease progression. AIDS 2011, 25(14):1711-1719. 10.1097/QAD.0b013e328349c693, 21681054.
113. Meehan AM, Saenz DT, Morrison J, Hu C, Peretz M, Poeschla EM. LEDGF dominant interference proteins demonstrate prenuclear exposure of HIV-1 integrase and synergize with LEDGF depletion to destroy viral infectivity. J Virol 2011, 85(7):3570-3583. 10.1128/JVI.01295-10, 3067863, 21270171.
114. De Luca L, Ferro S, Morreale F, Chimirri A. Inhibition of the interaction between HIV-1 integrase and its cofactor LEDGF/p75: a promising approach in anti-retroviral therapy. Mini Rev Med Chem 2011, 11(8):714-727.
115. Fenwick C, Bethell R, Cordingley M, Edwards P, Quinson A-M, Robinson P, Simoneau B, Yoakim C. BI 224436, a non-catalytic site integrase inhibitor, is a potent inhibitor of the replication of treatment-naïve and raltegravir-resistant clinical isolates of HIV-1. 51st Interscience Conference on Antimicrobials and Chemotherapy: 2011; Chicago, IL, USA; 2011 2011, Levin: Conference Reports for NATAP., http://www.natap.org/2011/ICAAC/ICAAC_34.htm
116. Aslanyan S, Ballow CH, Sabo JP, Habeck J, Roos D, MacGregor TR, Robinson P, Kort J. Safety and pharmacokinetics (PK) of single rising oral doses of a novel HIV integrase inhibitor in healthy volunteers. 51st Interscience Conference on Antimicrobials and Chemotherapy: 2011; Chicago, IL, USA; 2011 2011, Levin: Conference Reports for NATAP., http://www.natap.org/2011/ICAAC/ICAAC_35.htm
117. De Luca L, Ferro S, Morreale F, De Grazia S, Chimirri A. Inhibitors of the interactions between HIV-1 IN and the cofactor LEDGF/p75. ChemMedChem 2011, 6(7):1184-1191. 10.1002/cmdc.201100071, 21506277.
118. Tang J, Maddali K, Dreis CD, Sham YY, Vince R, Pommier Y, Wang Z. N-3 hydroxylation of pyrimidine-2,4-diones yields dual inhibitors of HIV reverse transcriptase and integrase. ACS Med Chem Lett 2011, 2(1):63-67. 10.1021/ml1002162, 3074239, 21499541.
119. Wang Z, Tang J, Salomon CE, Dreis CD, Vince R. Pharmacophore and structure-activity relationships of integrase inhibition within a dual inhibitor scaffold of HIV reverse transcriptase and integrase. Bioorg Med Chem 2010, 18(12):4202-4211. 10.1016/j.bmc.2010.05.004, 20576573.
120. 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(22):3335-3342. 10.2174/092986711796504619, 21728968.
121. Brenner BG, Lowe M, Moisi D, Hardy I, Gagnon S, Charest H, Baril JG, Wainberg MA, Roger M. Subtype diversity associated with the development of HIV-1 resistance to integrase inhibitors. J Med Virol 2011, 83(5):751-759. 10.1002/jmv.22047, 21360548.
122. Loizidou EZ, Kousiappa I, Zeinalipour-Yazdi CD, van de Vijver DA, Kostrikis LG. Implications of HIV-1 M group polymorphisms on integrase inhibitor efficacy and resistance: genetic and structural in silico analyses. Biochemistry 2009, 48(1):4-6. 10.1021/bi8019349, 19090674.
123. Malet I, Fourati S, Charpentier C, Morand-Joubert L, Armenia D, Wirden M, Sayon S, van Houtte M, Ceccherini-Silberstein F, Brun-Vézinet F, Perno CF, Descamps D, Capt A, Calvez V, Marcelin AG. The HIV-1 integrase G118R mutation confers raltegravir resistance to the CRF02_AG HIV-1 subtype. J Antimicrob Chemother 2011, 66(12):2827-2830. 10.1093/jac/dkr389, 21933786.