An allosteric mechanism for inhibiting HIV-1 integrase with a small molecule

Molecular Pharmacology

Volumn 76, Issue 4, 2009, Pages 824-832

  Kessl, Jacques J ^a   Eidahl, Jocelyn O ^a   Shkriabai, Nikolozi ^a   Zhao, Zhuojun ^a   McKee, Christopher J ^a   Hess, Sonja ^b   Burke Jr , Terrence R ^c   Kvaratskhelia, Mamuka ^a,d  

^a OHIO STATE UNIVERSITY   (United States)

^b CALIFORNIA INSTITUTE OF TECHNOLOGY   (United States)

^c NATIONAL CANCER INSTITUTE   (United States)

^d OHIO STATE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,3 BIS[[3 [3,4 BIS(ACETYLOXY)PHENYL] 1 OXO 2 PROPEN 1 YL]OXY]BUTANEDIOIC ACID; 3 [3,4 BIS(ACETOXY)PHENYL] 2 PROPENOATE N [3 [3,4 BIS(ACETYLOXY)PHENYL] 1 OXO 2 PROPENYL]SERINE METHYL ESTER; GROWTH FACTOR; INTEGRASE; INTEGRASE INHIBITOR; LYSINE; NUCLEOPROTEIN; UNCLASSIFIED DRUG;

ARTICLE; COMPLEX FORMATION; DRUG BINDING; DRUG STRUCTURE; EPITHELIUM; HUMAN IMMUNODEFICIENCY VIRUS 1; HYDROGEN BOND; NONHUMAN; PRIORITY JOURNAL;

AMINO ACID SEQUENCE; CHROMATOGRAPHY, GEL; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; PEPTIDES; SPECTROMETRY, MASS, MATRIX-ASSISTED LASER DESORPTION-IONIZATION;

EID: 70349331248     PISSN: 0026895X     EISSN: 15210111     Source Type: Journal    
DOI: 10.1124/mol.109.058883     Document Type: Article

References (39)

1. Al-Mawsawi LQ, Christ F, Dayam R, Debyser Z, and Neamati N (2008) Inhibitory profile of a LEDGF/p75 peptide against HIV-1 integrase: insight into integrase-DNA complex formation and catalysis. FEBS Lett 582:1425-1430.
2. Al-Mawsawi LQ, Fikkert V, Dayam R, Witvrouw M, Burke TR Jr, Borchers CH, 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)
3. Busschots K, De Rijck J, Christ F, and Debyser Z (2009) In search of small molecules blocking interactions between HIV proteins and intracellular cofactors. Mol Biosyst 5:21-31.
4. Chen JC, Krucinski J, Miercke LJ, Finer-Moore JS, Tang AH, Leavitt AD, and Stroud RM (2000) 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 97:8233-8238. (Pubitemid 30639655)
5. Cherepanov P, Ambrosio AL, 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)
6. Cherepanov P, Devroe E, Silver PA, and Engelman A (2004) 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 279:48883-48892. (Pubitemid 39625769)
7. 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)
8. Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P, Lazzarin A, Clotet B, Kumar PN, Eron JE, et al. (2008) Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 359:355-365.
9. De Rijck J, Vandekerckhove L, Gijsbers R, Hombrouck A, Hendrix J, Vercammen J, Engelborghs Y, Christ F, and Debyser Z (2006) Overexpression of the lens epithelium-derived growth factor/p75 integrase binding domain inhibits human immunodeficiency virus replication. J Virol 80:11498-11509. (Pubitemid 44788865)
10. Dyda F, Hickman AB, Jenkins TM, Engelman A, Craigie R, and Davies DR (1994) Crystal structure of the catalytic domain of HIV-1 integrase: similarity to other polynucleotidyl transferases. Science 266:1981-1986.
11. Emiliani S, Mousnier A, Busschots K, Maroun M, Van Maele B, Tempé D, Vandekerckhove L, Moisant F, Ben-Slama L, Witvrouw M, et al. (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)
12. Engelman A, Bushman FD, and Craigie R (1993) Identification of discrete functional domains of HIV-1 integrase and their organization within an active multimeric complex. EMBO J 12:3269-3275. (Pubitemid 23232758)
13. Faure A, Calmels C, Desjobert C, Castroviejo M, Caumont-Sarcos A, Tarrago-Litvak L, Litvak S, and Parissi V (2005) HIV-1 integrase crosslinked oligomers are active in vitro. Nucleic Acids Res 33:977-986. (Pubitemid 41430518)
14. Goodsell DS and Olson AJ (1990) Automated docking of substrates to proteins by simulated annealing. Proteins 8:195-202. (Pubitemid 20363304)
15. Guiot E, Carayon K, Delelis O, Simon F, Tauc P, Zubin E, Gottikh M, Mouscadet JF, Brochon JC, and Deprez E (2006) Relationship between the oligomeric status of HIV-1 integrase on DNA and enzymatic activity. J Biol Chem 281:22707-22719. (Pubitemid 44242299)
16. Hare S, Shun MC, Gupta SS, Valkov E, Engelman A, and Cherepanov P (2009) A novel co-crystal structure affords the design of gain-of-function lentiviral integrase mutants in the presence of modified PSIP1/LEDGF/p75. PLoS Pathog 5:e1000259.
17. Hayouka Z, Rosenbluh J, Levin A, Loya S, Lebendiker M, Veprintsev D, Kotler M, Hizi A, Loyter A, and Friedler A (2007) Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium. Proc Natl Acad Sci U S A 104:8316-8321. (Pubitemid 47175485)
18. Hazuda DJ, Hastings JC, Wolfe AL, and Emini EA (1994) A novel assay for the DNA strand-transfer reaction of HIV-1 integrase. Nucleic Acids Res 22:1121-1122.
19. Healy EF, Sanders J, King PJ, and Robinson WE Jr (2009) A docking study of L-chicoric acid with HIV-1 integrase. J Mol Graph Model 27:584-589.
20. Hou Y, McGuinness DE, Prongay AJ, Feld B, Ingravallo P, Ogert RA, Lunn CA, and Howe JA (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)
21. King PJ and Robinson WE Jr (1998) Resistance to the anti-human immunodeficiency virus type 1 compound L-chicoric acid results from a single mutation at amino acid 140 of integrase. J Virol 72:8420-8424.
22. Li M, Mizuuchi M, Burke TR Jr, and Craigie R (2006) Retroviral DNA integration: reaction pathway and critical intermediates. EMBO J 25:1295-1304.
23. Lin Z, Neamati N, Zhao H, Kiryu Y, Turpin JA, Aberham C, Strebel K, Kohn K, Witvrouw M, Pannecouque C, et al. (1999) Chicoric acid analogues as HIV-1 integrase inhibitors. J Med Chem 42:1401-1414. (Pubitemid 29200876)
24. Llano M, Saenz DT, Meehan A, Wongthida P, Peretz M, Walker WH, Teo W, and Poeschla EM (2006a) An essential role for LEDGF/p75 in HIV integration. Science 314:461-464. (Pubitemid 44628966)
25. Llano M, Vanegas M, Hutchins N, Thompson D, Delgado S, and Poeschla EM (2006b) Identification and characterization of the chromatin-binding domains of the HIV-1 integrase interactor LEDGF/p75. J Mol Biol 360:760-773. (Pubitemid 43993915)
26. 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)
27. McKee CJ, Kessl JJ, Shkriabai N, Dar MJ, Engelman A, and KvaratskheliaM(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.
28. Molteni V, Greenwald J, Rhodes D, Hwang Y, Kwiatkowski W, Bushman FD, Siegel JS, and Choe S (2001) Identification of a small-molecule binding site at the dimer interface of the HIV integrase catalytic domain. Acta Crystallogr D Biol Crystallogr 57:536-544. (Pubitemid 32296029)
29. Pandey KK, Sinha S, and Grandgenett DP (2007) Transcriptional coactivator LEDGF/p75 modulates human immunodeficiency virus type 1 integrase-mediated concerted integration. J Virol 81:3969-3979. (Pubitemid 46586892)
30. Pluymers W, Neamati N, Pannecouque C, Fikkert V, Marchand C, Burke TR Jr, Pommier Y, Schols D, De Clercq E, Debyser Z, et al. (2000) Viral entry as the primary target for the anti-HIV activity of chicoric acid and its tetra-acetyl esters. Mol Pharmacol 58:641-648. (Pubitemid 30683006)
31. Raghavendra NK and Engelman A (2007) LEDGF/p75 interferes with the formation of synaptic nucleoprotein complexes that catalyze full-site HIV-1 DNA integration in vitro: implications for the mechanism of viral cDNA integration. Virology 360:1-5.
32. Shkriabai N, Patil SS, Hess S, Budihas SR, Craigie R, Burke TR Jr, Le Grice SF, and Kvaratskhelia M (2004) Identification of an inhibitor-binding site to HIV-1 integrase with affinity acetylation and mass spectrometry. Proc Natl Acad Sci U S A 101:6894-6899. (Pubitemid 38596414)
33. Shun MC, Raghavendra NK, Vandegraaff N, Daigle JE, Hughes S, Kellam P, Cherepanov P, and Engelman A (2007) LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev 21:1767-1778. (Pubitemid 47076476)
34. Summa V, Petrocchi A, Bonelli F, Crescenzi B, Donghi M, Ferrara M, Fiore F, Gardelli C, Gonzalez Paz O, Hazuda DJ, et al. (2008) Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J Med Chem 51:5843-5855.
35. van den Ent FM, Vos A, and Plasterk RH (1999) Dissecting the role of the N-terminal domain of human immunodeficiency virus integrase by trans-complementation analysis. J Virol 73:3176-3183. (Pubitemid 29135709)
36. van Gent DC, Vink C, Groeneger AA, and Plasterk RH (1993) Complementation between HIV integrase proteins mutated in different domains. EMBO J 12:3261-3267. (Pubitemid 23232757)
37. Vanegas M, Llano M, Delgado S, Thompson D, Peretz M, and Poeschla E (2005) Identification of the LEDGF/p75 HIV-1 integrase-interaction domain and NLS reveals NLS-independent chromatin tethering. J Cell Sci 118:1733-1743. (Pubitemid 40691901)
38. Wang JY, Ling H, Yang W, and Craigie R (2001) Structure of a two-domain fragment of HIV-1 integrase: implications for domain organization in the intact protein. EMBO J 20:7333-7343. (Pubitemid 34062324)
39. Zhao Z, McKee CJ, Kessl JJ, Santos WL, Daigle JE, Engelman A, Verdine G, and Kvaratskhelia M (2008) Subunit-specific protein footprinting reveals significant structural rearrangements and a role for N-terminal Lys-14 of HIV-1 Integrase during viral DNA binding. J Biol Chem 283:5632-5641.