Small-molecule inhibitors of the LEDGF/p75 binding site of integrase block HIV replication and modulate integrase multimerization

Antimicrobial Agents and Chemotherapy

Volumn 56, Issue 8, 2012, Pages 4365-4374

  Christ, Frauke ^a   Shaw, Stephen ^b,e   Demeulemeester, Jonas ^a   Desimmie, Belete A ^a   Marchan, Arnaud ^c   Butler, Scott ^b,d   Smets, Wim ^c   Chaltin, Patrick ^a,c   Westby, Mike ^b,f   Debyser, Zeger ^a   Pickford, Chris ^b,e  

^a UNIVERSITY OF LEUVEN   (Belgium)

^b PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

^c CISTIM   (Belgium)

^d ASTRAZENECA   (United Kingdom)

^e Research Network   (United Kingdom)

^f Loxbridge Research LLC   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2 (QUINOLIN 3 YL)ACETIC ACID DERIVATIVE; INTEGRASE; INTEGRASE INHIBITOR; UNCLASSIFIED DRUG;

ANTIVIRAL ACTIVITY; ARTICLE; BINDING SITE; CATALYSIS; CONTROLLED STUDY; DRUG MECHANISM; DRUG PROTEIN BINDING; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS 1; NONHUMAN; OLIGOMERIZATION; PRIORITY JOURNAL; PROTEIN MULTIMERIZATION; VIRUS DNA CELL DNA INTERACTION; VIRUS REPLICATION;

BINDING SITES; CATALYTIC DOMAIN; CELL LINE; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HIV-1; HUMANS; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; PROTEIN MULTIMERIZATION; PYRROLIDINONES; QUINOLINES; VIRUS INTEGRATION; VIRUS REPLICATION;

EID: 84864387134     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.00717-12     Document Type: Article

References (49)

1. Adachi A, et al. 1986. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J. Virol. 59:284-291. (Pubitemid 16013975)
2. Blair WS, et al. 2010. HIV capsid is a tractable target for small molecule therapeutic intervention. PLoS Pathog. 6:e1001220. doi:10.1371/journal. ppat.1001220.
3. Bruno R, Sacchi P, Filice G. 2003. Didanosine-ribavirin combination: synergistic combination in vitro, but high potential risk of toxicity in vivo. AIDS 17:2674-2675. (Pubitemid 38402350)
4. Busschots K, et al. 2005. The interaction of LEDGF/p75 with integrase is lentivirus-specific and promotes DNA binding. J. Biol. Chem. 280:17841-17847. (Pubitemid 41389024)
5. Chen JC, et al. 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)
6. Cherepanov P, Ambrosio AL, Rahman S, Ellenberger T, 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)
7. Cherepanov P, Devroe E, Silver PA, 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)
8. Cherepanov P, et al. 2003. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J. Biol. Chem. 278:372-381. (Pubitemid 36043586)
9. Christ F, et al. 2010. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat. Chem. Biol. 6:442-448.
10. Corbau R, et al. 2010. Lersivirine, a nonnucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 54:4451-4463.
11. Demeulemeester J, Tintori C, Botta M, Debyser Z, Christ F. 2012. Development of an AlphaScreen-based HIV-1 integrase dimerization assay for discovery of novel allosteric inhibitors. J. Biomol. Screen. 17:618-628.
12. De Rijck J, et al. 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)
13. Desimmie BA, et al. Phage display-directed discovery of LEDGF/p75 binding cyclic peptide inhibitors of HIV replication. Mol. Ther., in press.
14. Desimmie BA, Schrijvers R, Debyser Z. 2012. Elvitegravir: a once daily alternative to raltegravir. Lancet Infect. Dis. 12:3-5.
15. Emiliani S, 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)
16. Espeseth AS, et al. 2000. 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. 97:11244-11249.
17. Garrido C, et al. 2011. Resistance associated mutations to dolutegravir (S/GSK1349572) in HIV-infected patients - impact of HIV subtypes and prior raltegravir experience. Antiviral Res. 90:164-167.
18. Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P. 2010. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464:232-236.
19. Hayouka Z, et al. 2007. Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium. Proc. Natl. Acad. Sci. U. S. A. 104:8316-8321. (Pubitemid 47175485)
20. Hombrouck A, et al. 2007. Virus evolution reveals an exclusive role for LEDGF/p75 in chromosomal tethering of HIV. PLoS Pathog. 3:e47. doi: 10.1371/journal.ppat.0030047.
21. Johnson EN, et al. 2008. A 1,536-well [(35)S]GTPgammaS scintillation proximity binding assay for ultra-high-throughput screening of an orphan Galphai-coupled GPCR. Assay Drug Dev. Technol. 6:327-337.
22. Kessl JJ, et al. 2009. An allosteric mechanism for inhibiting HIV-1 integrase with a small molecule. Mol. Pharmacol. 76:824-832.
23. Kessl JJ, et al. 2012. A multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors. J. Biol. Chem. 287:16801-16811.
24. Kessl JJ, et al. 2011. FRET analysis reveals distinct conformations of IN tetramers in the presence of viral DNA or LEDGF/p75. Nucleic Acids Res. 39:9009-9022.
25. Lewinski MK, et al. 2006. Retroviral DNA integration: viral and cellular determinants of target-site selection. PLoS Pathog. 2:e60.
26. Llano M, et al. 2006. An essential role for LEDGF/p75 in HIV integration. Science 314:461-464. (Pubitemid 44628966)
27. Maertens G, Cherepanov P, Debyser Z, Engelborghs Y, Engelman A. 2004. Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75. J. Biol. Chem. 279:33421-33429. (Pubitemid 39062991)
28. Malet I, et al. 2008. Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob. Agents Chemother. 52:1351-1358. (Pubitemid 351521998)
29. Margot NA, Miller MD. 2005. In vitro combination studies of tenofovir and other nucleoside analogues with ribavirin against HIV-1. Antivir. Ther. 10:343-348. (Pubitemid 41151041)
30. Marinello J, et al. 2008. Comparison of raltegravir and elvitegravir on HIV-1 integrase catalytic reactions and on a series of drug-resistant integrase mutants. Biochemistry 47:9345-9354.
31. McNeely M, et al. 2011. In vitro DNA tethering of HIV-1 integrase by the transcriptional coactivator LEDGF/p75. J. Mol. Biol. 410:811-830.
32. Molina JM, et al. 2012. Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study. Lancet Infect. Dis. 12:27-35.
33. Murray JM, et al. 2007. Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase. AIDS 21:2315-2321. (Pubitemid 350287458)
34. Neamati N, ed. 2011. HIV-1 integrase: mechanism and inhibitor design. Wiley Series in Drug Discovery and Development. John Wiley & Sons, Hoboken, NJ.
35. Niesen FH, Berglund H, Vedadi M. 2007. The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability. Nat. Protoc. 2:2212-2221. (Pubitemid 351565860)
36. Pauwels R, et al. 1990. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature 343:470-474. (Pubitemid 120028562)
37. Pauwels R, et al. 1988. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J. Virol. Methods 20:309-321.
38. Petropoulos CJ, et al. 2000. A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 44:920-928. (Pubitemid 30165271)
39. Schrijvers R, et al. 2012. LEDGF/p75-independent HIV-1 replication demonstrates a role for HRP-2 and remains sensitive to inhibition by LEDGINs. PLoS Pathog. 8:e1002558. doi:10.1371/journal.ppat.1002558.
40. Shimura K, et al. 2008. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J. Virol. 82:764-774.
41. Shun MC, et al. 2007. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev. 21:1767-1778.
42. Summa V, 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.
43. Tintori C, et al. 2012. Discovery of small molecule HIV-1 integrase dimerization inhibitors. Bioorg. Med. Chem. Lett. 22:3109-3114.
44. Tsiang M, et al. 25 April 2012. New class of HIV-1 integrase (IN) inhibitors with a dual mode of action. J. Biol. Chem. doi:10.1074/jbc.M112. 347534.
45. Vandekerckhove L, et al. 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)
46. Vanegas M, et al. 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)
47. Wang GP, Ciuffi A, Leipzig J, Berry CC, Bushman FD. 2007. HIV integration site selection: analysis by massively parallel pyrosequencing reveals association with epigenetic modifications. Genome Res. 17:1186-1194. (Pubitemid 47204862)
48. Zeier MD, Nachega JB. 2011. Targeting HIV: past, present and future. Infect. Disord. Drug Targets 11:98-114.
49. Zolopa AR, et al. 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.