Targeting the HIV integration process in antiviral therapy

Journal of HIV Therapy

Volumn 13, Issue 4, 2008, Pages 83-92

  Mcneely, Melissa ^a   Christ, Frauke ^a   Thys, Wannes ^a   Debyser, Zeger ^a  

^a NONE

Author keywords

[No Author keywords available]

Indexed keywords

5H PYRANO [2,3 D:6,5D'] DIPYRIMIDINE DERIVATIVE; ANTIVIRUS AGENT; CD4 ANTIGEN; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CXCR4; D 77; ELVITEGRAVIR; ENFUVIRTIDE; GLYCOPROTEIN GP 120; INTEGRASE; LENS EPITHELIUM DERIVED GROWTH FACTOR; MARAVIROC; PROTEIN P75; PROTEINASE INHIBITOR; RALTEGRAVIR; RNA DIRECTED DNA POLYMERASE; RNA DIRECTED DNA POLYMERASE INHIBITOR; STYRYLQUINOLONE DERIVATIVE; TRICYCLIC 10 HYDROXY 7,8 DIHYDROPYRAZINOPYRROLOPYRAZINE 1,9 DIONE; UNCLASSIFIED DRUG; 2 PYRROLIDONE DERIVATIVE; INTEGRASE INHIBITOR; QUINOLONE DERIVATIVE;

ANTIVIRAL ACTIVITY; BINDING AFFINITY; BINDING SITE; CARBOXY TERMINAL SEQUENCE; CLINICAL TRIAL; CONFERENCE PAPER; CYTOPLASM; CYTOTOXICITY; DNA BINDING; DNA REPAIR; DNA SYNTHESIS; DRUG EFFICACY; DRUG TARGETING; EMBRYO DEVELOPMENT; ENZYME ACTIVITY; ENZYME INHIBITION; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HYDROXYLATION; LONG TERMINAL REPEAT; NONHUMAN; PHOTOAFFINITY LABELING; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN MOTIF; PROTEIN PROTEIN INTERACTION; TERATOGENICITY; TRANSESTERIFICATION; VIRUS DNA CELL DNA INTERACTION; VIRUS GENOME; VIRUS REPLICATION; VIRUS STRAIN; DRUG EFFECT; ENZYMOLOGY; GENETICS; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; REVIEW; VIROLOGY;

HIV; HIV INFECTIONS; HIV INTEGRASE INHIBITORS; HUMANS; PYRROLIDINONES; QUINOLONES; VIRUS INTEGRATION;

EID: 65649084133     PISSN: 14620308     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Conference Paper

References (91)

1. Ryan DP, JM Matthews. Protein-protein interactions in human disease. Curr Opin Struct Biol, 2005, 15, 441-446.
2. Arkin MR, Wells JA. Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat Rev Drug Discov, 2004, 3, 301-317.
3. Berg T. Modulation of protein-protein interactions with small organic molecules. Angew Chem Int Ed Engl, 2003, 42, 2462-2481.
4. Brass AL, Dykxhoorn DM, Benita Y et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science, 2008, 319, 921-926.
5. Cherepanov P, Maertens G, Proost P et al. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J Biol Chem, 2003, 278, 372-381.
6. Christ F, Thys W, De Rijck J et al. Transportin-SR2 imports HIV into the nucleus. Curr Biol, 2008, 18, 1192-1202.
7. Voight PK. Historical introduction to the general properties of retroviruses. In: Coffin JM, Hughes SH, Varmus HE, eds. Retroviruses. Cold Spring Harbor Laboratory Press, New York, 1997, pp 1-25.
8. Llano M, Delgado S, Vanegas M et al. Lens epithelium-derived growth factor/p75 prevents proteasomal degradation of HIV-1 integrase. J Biol Chem, 2004, 279, 55570-55577.
9. Ciuffi A, Bushman FD. Retroviral DNA integration: HIV and the role of LEDGF/p75. Trends Genet, 2006, 22, 388-395.
10. Pommier Y, Marchand C, Neamati N. Retroviral integrase inhibitors year 2000: update and perspectives. Antiviral Res, 2000, 47, 139-148.
11. Witvrouw M, Van Maele B, Vercammen J et al. Novel inhibitors of HIV-1 integration. Curr Drug Metab, 2004, 5, 291-304.
12. Young SD, Inhibition of HIV-1 integrase by small molecules: the potential for a new class of AIDS chemotherapeutics. Curr Opin Drug Discov Devel, 2001, 4, 402-410.
13. Pannecouque C, Pluymers W, Van Maele B et al. New class of HIV integrase inhibitors that block viral replication in cell culture. Curr Biol, 2002, 12, 1169-1177.
14. Deprez E, Barbe S, Kolaski M et al. Mechanism of HIV-1 integrase inhibition by styrylquinoline derivatives in vitro. Mol Pharmacol, 2004, 65, 85-98.
15. Van Maele B, De Rijck J, De Clercq E et al. Impact of the central polypurine tract on the kinetics of human immunodeficiency virus type 1 vector transduction. J Virol, 2003, 77, 4685-4694.
16. Hombrouck A, Hantson A, van Remoortel B et al. Selection of human immunodeficiency virus type 1 resistance against the pyranodipyrimidine V-165 points to a multimodal mechanism of action. J Antimicrob Chemother, 2007, 59, 1084-1095.
17. Bonnenfant S, Thomas CM, Vita C et al. Styrylquinolines, integrase inhibitors acting prior to integration: a new mechanism of action for anti-integrase agents. J Virol, 2004, 78, 5728-5736.
18. Mousnier A, Leh H, Mouscadet JF et al. Nuclear import of HIV-1 integrase is inhibited in vitro by styrylquinoline derivatives. Mol Pharmacol, 2004, 66, 783-788.
19. Grinsztejn B, Nguyen BY, Katlama C et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatmentexperienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet, 2007, 369, 1261-1269.
20. Kassahun K, McIntosh I, Cui D et al. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos, 2007, 35, 1657-1663.
21. Markowitz M, Morales-Ramirez JO, Nguyen BY et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr, 2006, 43, 509-515.
22. Merschman SA, Vallano T, Wenning LA et al. Determination of the HIV integrase inhibitor, MK-0518 (raltegravir), in human plasma J Chromatogr B Analyt Technol Biomed Life Sci, 2007, 857, 15-24.
23. Hazuda, D.J., Felock, M. Witmer et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science, 2000, 287, 646-650.
24. Goldgur Y, Craigie R, Cohen GH et al. 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.
25. Espeseth A, Felock S, Wolfe A et al. 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.
26. Grobler JA, Stillmock K, Hu B et al. Diketo acid inhibitor mechanism and HIV-1 integrase: implications for metal binding in the active site of phosphotransferase enzymes. Proc Natl Acad Sci U S A, 2002, 99, 6661-6666.
27. Pommier Y, Johnson AA, Marchand C. Integrase inhibitors to treat HIV/AIDS. Nat Rev Drug Discov, 2005, 4, 236-248.
28. Steigbigel RT, Cooper DA, Kumar N et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med, 2008, 359, 339-354.
29. Hazuda DJ, Miller MD, Nguyen BY et al. Resistance to the HIV -integrase inhibitor raltegravir: analysis of protocol 005, a Phase II study in patients with triple-class resistant HIV-1 infection. Antiviral Ther, 2007, 12, S10.
30. Marinello J, Marchand C, Mott BT et al. Comparison of raltegravir and elvitegravir on HIV-1 integrase catalytic reactions and on a series of drug-resistant integrase mutants. Biochemistry, 2008, 47, 9345-9354.
31. Charpentier C, Karmochkine M, Laureillard D et al. Drug resistance profiles for the HIV integrase gene in patients failing raltegravir salvage therapy. HIV Med, 2008, 9, 765-770.
32. Goethals O, Clayton R, Van Ginderen M et al. 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.
33. Shimura K, Kodama E, Sakagami Y et al. 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.
34. Al-Mawsawi LQ, Al-Safi RI, Neamati N. Anti-infectives: clinical progress of HIV-1 integrase inhibitors. Exp Opin Emerg Drugs, 2008, 13, 213-225.
35. Van Maele B, Busschots K, Vandekerckhove L et al. Cellular co-factors of HIV-1 integration. Trends Biochem Sci, 2006, 31, 98-105.
36. De Rijck J, Vandekerckhove L, Gijsbers R et al. Overexpression of the lens epithelium-derived growth factor/p75 integrase binding domain inhibits human immunodeficiency virus replication. J Virol, 2006, 80, 11498-11509.
37. Llano M, Saenz DT, Meehan A et al. An essential role for LEDGF/p75 in HIV integration. Science, 2006, 314, 461-464.
38. Vandekerckhove L, Christ F, Van Maele B et al. Transient and stable knockdown of the integrase cofactor LEDGF/p75 reveals its role in the replication cycle of human immunodeficiency virus. J Virol, 2006, 80, 1886-1896.
39. Maertens G, Cherepanov P, Pluymers W et al. LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. J Biol Chem, 2003, 278, 33528-33539.
40. Cherepanov P, Devroe E, Silver A et al. Identification of an evolutionarily conserved domain in human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) that binds HIV-1 integrase. J Biol Chem, 2004, 279, 48883-48892.
41. Llano M, Vanegas M, Fregoso O et al. LEDGF/p75 determines cellular trafficking of diverse lentiviral but not murine oncoretroviral integrase proteins and is a component of functional lentiviral preintegration complexes. J Virol, 2004, 78, 9524-9537.
42. Maertens G, Cherepanov P, Debyser Z et al. Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75. J Biol Chem, 2004, 279, 33421-33429.
43. Busschots K, Vercammen J, Emiliani S et al. The interaction of LEDGF/p75 with integrase is lentivirus-specific and promotes DNA binding. J Biol Chem, 2005, 280, 17841-17847.
44. Ciuffi A, Llano M, Poeschla E et al. A role for LEDGF/p75 in targeting HIV DNA integration. Nat Med, 2005, 11, 1287-1289.
45. Logtenberg T. Antibody cocktails: next-generation biopharmaceuticals with improved potency. Trends Biotechnol, 2007, 25, 390-394.
46. Adessi C, Soto C. Converting a peptide into a drug: strategies to improve stability and bioavailability. Curr Med Chem, 2002, 9, 963-978.
47. Wells JA, McClendon CL. Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature, 2007, 450, 1001-1009.
48. Kilby JM, Hopkins S, Venetta TM et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med, 1998, 4, 1302-1307.
49. Dorr P, Westby M, Dobbs S et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother, 2005, 49, 4721-4732.
50. Franke EK, Luban J. Inhibition of HIV-1 replication by cyclosporine A or related compounds correlates with the ability to disrupt the Gagcyclophilin A interaction. Virology, 1996, 222, 279-282.
51. Streblow D, Kitabwalla N, Malkovsky M et al. Cyclophilin a modulates processing of human M immunodeficiency virus type 1 p55Gag: mechanism for antiviral effects of cyclosporin A. Virology, 1998, 245, 197-202.
52. Bartz SR, Hohenwalter E, Hu MK et al. Inhibition of human immunodeficiency virus replication by nonimmunosuppressive analogs of cyclosporin A. Proc Natl Acad Sci U S A, 1995, 92, 5381-5385.
53. Watashi K, Ishii N, Hijikata M et al. Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol Cell, 2005, 19, 111-122.
54. Ma S, Boerner JE, TiongYip C et al. NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon. Antimicrob Agents Chemother, 2006, 50, 2976-2982.
55. Flisiak R, Dumont JM, Crabbe R. Cyclophilin inhibitors in hepatitis C viral infection. Exp Opin Invest Drugs, 2007, 16, 1345-1354.
56. Flisiak R, Horban A, Gallay P et al. The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology, 2008, 47, 817-826.
57. Yoakim C, Ogilvie WW, Goudreau N et al. Discovery of the first series of inhibitors of human papillomavirus type 11: inhibition of the assembly of the E1-E2-Origin DNA complex. Bioorg Med Chem Lett, 2003, 13, 2539-2541.
58. White W, Titolo S, Brault K et al. Inhibition of human papillomavirus DNA replication by small molecule antagonists of the E1-E2 protein interaction. J Biol Chem, 2003, 278, 26765-26772.
59. Wang Y, Coulombe R, Cameron DR et al. Crystal structure of the E2 transactivation domain of human papillomavirus type 11 bound to a protein interaction inhibitor. J Biol Chem, 2004, 279, 6976-6985.
60. Llano M, Vanegas M, Fregoso O et al. LEDGF/p75 determines cellular trafficking of diverse lentiviral but not murine oncoretroviral integrase proteins and is a component of functional lentiviral preintegration complexes. J Virol, 2004, 78, 9524-9537.
61. Emiliani S, Mousnier A, Busschots K et al. Integrase mutants defective for interaction with LEDGF/p75 are impaired in chromosome tethering and HIV-1 replication. J Biol Chem, 2005, 280, 25517-25523.
62. Shun MC, Daigle JE, Vandegraaff N et al. Wild-type levels of human immunodeficiency virus type 1 infectivity in the absence of cellular emerin protein. J Virol, 2007, 81, 166-172.
63. Busschots K, Voet A, De Maeyer M et al. Identification of the LEDGF/p75 Binding Site in HIV-1 Integrase. J Mol Biol, 2007, 365, 1480-1492.
64. Rahman S, Lu R, Vandegraaff N et al. Structure-based mutagenesis of the integrase-LEDGF/p75 interface uncouples a strict correlation between in vitro protein binding and HIV-1 fitness. Virology, 2007, 357, 79-90.
65. Marshall HM, Ronen K, Berry C et al. Role of PSIP1/LEDGF/p75 in lentiviral infectivity and integration targeting. PL0S ONE, 2007, 2, e1340.
66. Singh DP, Fatma N, Kimura A et al. LEDGF binds to heat shock and stress-related element to activate the expression of stress-related genes. Biochem Biophys Res Commun, 2001, 283, 943-955.
67. Shinohara T, Singh DP, Fatma N. LEDGF, a survival factor, activates stress- related genes. Prog Retin Eye Res, 2002, 21, 341-358.
68. Llano M, Vanegas M, Hutchins N et al. Identification and characterization of the chromatin-binding domains of the HIV-1 integrase interactor LEDGF/p75. J Mol Biol, 2006. 360, 760-773.
69. Hombrouck A, De Rijck J, Hendrix J et al. Virus evolution reveals an exclusive role for LEDGF/p75 in chromosomal tethering of HIV. PL0S Pathog, 2007, 3, e47.
70. Shun MC, Raghavendra NK, Vandegraaff N et al. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev, 2007, 21, 1767-1778.
71. Busschots K, Voet A, De Maeyer M et al. Identification of the LEDGF/p75 binding site in HIV-1 integrase. J Mol Biol, 2007, 365, 1480-1492.
72. Cherepanov P, Sun ZY, Rahman S et al. Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75. Nat Struct Mol Biol, 2005, 12, 526-532.
73. Asante-Appiah E, Skalka AM. HIV-1 integrase: structural organization, conformational changes, and catalysis. Adv Virus Res, 1999, 52, 351-369.
74. Engelman A, Craigie R. Identification of conserved amino acid residues critical for human immunodeficiency virus type 1 integrase function in vitro. J Virol, 1992, 66, 6361-6369.
75. Engelman A, Bushman FD, Craigie R. Identification of discrete functional domains of HIV-1 integrase and their R organization within an active multimeric complex. EMBO J, 1993, 12, 3269-3275.
76. Bushman FD, Wang B. Rous sarcoma virus integrase protein: mapping functions for catalysis and substrate binding. J Virol, 1994, 68, 2215-2223.
77. Jenkins TM, Engelman A, Ghirlando R et al. A soluble active mutant of HIV-1 integrase: involvement of both the core and carboxylterminal domains in multimerization. J Biol Chem, 1996, 271, 7712-7718.
78. Botbol Y, Raghavendra NK, Rahman S et al. Chromatinized templates reveal the requirement for the LEDGF/p75 PWWP domain during HIV-1 integration in vitro. Nucl Acid Res, 2008, 36, 1237-1246.
79. Turlure F, Maertens G, Rahman S et al. A tripartite DNA-binding element, comprised of the nuclear localization signal and two AT-hook motifs, mediates the association of LEDGF/p75 with chromatin in vivo. Nucleic Acids Res, 2006, 34, 1663-1675.
80. Vanegas M, Llano M, Delgado S et al. Identification of the LEDGF/p75 HIV-1 integrase-interaction domain and NLS reveals NLS-independent chromatin tethering. J Cell Sci, 2005, 118, 1733-1743.
81. Singh DP, Kimura A, Chylack Jr LT et al. Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing. Gene, 2000, 242, 265-273.
82. Ge H, Si Y, Roeder RG. Isolation of cDNAs encoding novel transcription coactivators p52 and p75 reveals an alternate regulatory mechanism of transcriptional activation. EMBO J, 1998, 17, 6723-6729.
83. Cherepanov P, Ambrosio AL, Rahman S et al. Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc Natl Acad Sci USA, 2005, 102, 17308-17313.
84. Sutherland HG, Newton K, Brownstein DG et al. Disruption of Ledgf/Psip1 results in perinatal mortality and homeotic skeletal transformations. Mol Cell Biol, 2006, 26, 7201-7210.
85. Wu X, Daniels T, Molinaro C et al. Caspase cleavage of the nuclear autoantigen LEDGF/p75 abrogates its pro-survival function, implications for autoimmunity in atopic disorders. Cell Death Differ, 2002, 9, 915-925.
86. Bartholomeeusen K, De Rijck J, Busschots K et al. Differential interaction of HIV-1 integrase and JPO2 with the C terminus of LEDGF/p75. J Mol Biol, 2007, 372, 407-421.
87. Maertens GN, 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.
88. Molteni V, Greenwald J, Rhodes D et al. Identification of a small-molecule binding site at the dimer interface of the HIV integrase catalytic domain. Acta Crystallogr D Biol Crystallogr, 2001, 57, 536-544.
89. Al-Mawsawi LQ, Christ F, Dayam R et al. 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.
90. Du L, Zhao Y, Chen J et al. D77, one benzoic acid derivative, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular LEDGF/p75. Biochem Biophys Res Commun, 2008, 375, 139-144.
91. Hou Y, McGuinness DE, Prongay AJ et al. Screening for antiviral inhibitors of the HIV integrase-LEDGF/p75 interaction using the AlphaScreen luminescent proximity assay. J Biomol Screen, 2008, 13, 406-414.