Preclinical profile of BI 224436, a novel hiv-1 non-catalytic-site integrase inhibitor

Antimicrobial Agents and Chemotherapy

Volumn 58, Issue 6, 2014, Pages 3233-3244

  Fenwick, Craig ^a   Amad, Ma'an ^a   Bailey, Murray D ^a   Bethell, Richard ^a   Bös, Michael ^a   Bonneau, Pierre ^a   Cordingley, Michael ^a   Coulombe, René ^a   Duan, Jianmin ^a   Edwards, Paul ^a   Fader, Lee D ^a   Faucher, Anne Marie ^a   Garneau, Michel ^a   Jakalian, Araz ^a   Kawai, Stephen ^a   Lamorte, Louie ^a   LaPlante, Steven ^a   Luo, Laibin ^a   Mason, Steve ^a   Poupart, Marc André ^a   Rioux, Nathalie ^a   Schroeder, Patricia ^a   Simoneau, Bruno ^a   Tremblay, Sonia ^a   Tsantrizos, Youla ^a   Witvrouw, Myriam ^a   Yoakim, Christiane ^a   more..

^a BOEHRINGER INGELHEIM CANADA LTD   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ABACAVIR; AMPRENAVIR; ATAZANAVIR; BI 224436; DARUNAVIR; DIDANOSINE; DOLUTEGRAVIR; EFAVIRENZ; ELVITEGRAVIR; EMTRICITABINE; ETRAVIRINE; FURAFYLLINE; HUMAN IMMUNODEFICIENCY VIRUS PROTEINASE INHIBITOR; INDINAVIR; KETOCONAZOLE; LAMIVUDINE; LOPINAVIR; MARAVIROC; NELFINAVIR; NEVIRAPINE; RALTEGRAVIR; RITONAVIR PLUS SAQUINAVIR; STAVUDINE; SULFAPHENAZOLE; TENOFOVIR; TIPRANAVIR; TRANYLCYPROMINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; ZIDOVUDINE; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; CYTOCHROME P450 INHIBITOR; INTEGRASE; INTEGRASE INHIBITOR; P31 INTEGRASE PROTEIN, HUMAN IMMUNODEFICIENCY VIRUS 1; VIRUS DNA;

ALLOSTERISM; ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CELL MEDIATED CYTOTOXICITY; DOSE RESPONSE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENTIATION; DRUG SOLUBILITY; FEMALE; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; IC 50; IN VITRO STUDY; IN VIVO STUDY; LIMIT OF QUANTITATION; LIQUID CHROMATOGRAPHY; LONG TERMINAL REPEAT; MALE; MASS SPECTROMETRY; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; PRIORITY JOURNAL; RAT; AMINO ACID SUBSTITUTION; ANIMAL; ANTIVIRAL RESISTANCE; BIOSYNTHESIS; CACO 2 CELL LINE; DRUG EFFECTS; ENZYMOLOGY; GENETICS; LIVER CELL; METABOLISM; MOLECULAR CLONING; MOUSE; PHYSIOLOGY; SERUM; VIROLOGY; VIRUS REPLICATION;

AMINO ACID SUBSTITUTION; ANIMALS; ANTI-HIV AGENTS; CACO-2 CELLS; CLONING, MOLECULAR; CYTOCHROME P-450 ENZYME INHIBITORS; DNA, VIRAL; DRUG RESISTANCE, VIRAL; HEPATOCYTES; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HIV-1; HUMANS; MICE; RATS; SERUM; VIRUS REPLICATION;

EID: 84901253412     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.02719-13     Document Type: Article

References (55)

1. Asante-Appiah E, Skalka AM. 1999. HIV-1 integrase: structural organization, conformational changes, and catalysis. Adv. Virus Res. 52:351-369. http://dx.doi.org/10.1016/S0065-3527(08)60306-1.
2. Bushman FD, Craigie R. 1991. Activities of human immunodeficiency virus (HIV) integration protein in vitro: specific cleavage and integration of HIV DNA. Proc. Natl. Acad. Sci. U. S. A. 88:1339-1343. http://dx.doi.org/10.1073/ pnas.88.4.1339.
3. Maertens G, Cherepanov P, Pluymers W, Busschots K, De Clercq E, Debyser Z, 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. http://dx.doi.org/10.1074/jbc.M303594200.
4. Llano M, Vanegas M, Fregoso O, Saenz D, Chung S, Peretz M, Poeschla EM. 2004. 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. 78:9524-9537. http://dx.doi.org/10.1128/JVI.78.17.9524-9537.2004.
5. Llano M, Saenz DT, Meehan A, Wongthida P, Peretz M, Walker WH, Teo W, Poeschla EM. 2006. An essential role for LEDGF/p75 in HIV integration. Science 314:461-464. http://dx.doi.org/10.1126/science.1132319.
6. Hombrouck A, De Rijck J, Hendrix J, Vandekerckhove L, Voet A, De Maeyer M, Witvrouw M, Engelborghs Y, Christ F, Gijsbers R, Debyser Z. 2007. Virus evolution reveals an exclusive role for LEDGF/p75 in chromosomal tethering of HIV. PLoS Pathog. 3:e47. http://dx.doi.org/10.1371/journal.ppat.0030047.
7. Poeschle E. 2008. Integrase, LEDGF/p75 and HIV replication. Cell. Mol. Life Sci. 65:1403-1424. http://dx.doi.org/10.1007/s00018-008-7540-5.
8. Hazuda DJ, Felock P, Witmer M, Wolfe A, Stillmock K, Grobler JA, Espeseth A, Gabryelski L, Schleif W, Blau C, Miller MD. 2000. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287:646-650. http://dx.doi.org/10.1126/science.287.5453.646.
9. Métifiot M, Maddali K, Naumova A, Zhang X, Marchand C, Pommier Y. 2010. Biochemical and pharmacological analyses of HIV-1 integrase flexible loop mutants resistant to raltegravir. Biochemistry 49:3715-3722. http://dx.doi.org/10.1021/bi100130f.
10. Espeseth AS, Felock P, Wolfe A, Witmer M, Grobler J, Anthony N, Egbertson M, Melamed JY, Young S, Hamill T, Cole JL, Hazuda DJ. 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. http://dx.doi.org/10.1073/pnas.200139397.
11. Grobler JA, Stillmock K, Hu B, Witmer M, Felock P, Espeseth AS, Wolfe A, Egbertson M, Bourgeois M, Melamed J, Wai JS, Young S, Vacca J, Hazuda DJ. 2002. 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. 99:6661-6666. http://dx.doi.org/10.1073/pnas.092056199.
12. Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P. 2010. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464:232-236. http://dx.doi.org/10.1038/nature08784.
13. 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. 2008. Resistance mutations in human immunodeficiency virus type 1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors. J. Virol. 82:10366-10374. http://dx.doi.org/10.1128/JVI.00470-08.
14. Marinello J, Marchand C, Mott BT, Bain A, Thomas CJ, Pommier Y. 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. http://dx.doi.org/10.1021/bi800791q.
15. Shimura K, Kodama EN. 2009. Elvitegravir: a new HIV integrase inhibitor. Antivir. Chem. Chemother. 20:79-85. http://dx.doi.org/10.3851/IMP1397.
16. Zolopa AR, Berger DS, Lampiris H, Zhong L, Chuck SL, Enejosa JV, Kearney BP, Cheng AK. 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. http://dx.doi.org/10. 1086/650698.
17. Mascolinli M, Kort R. 2010. Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention: summary of key research and implications for policy and practice-clinical sciences. J. Int. AIDS Soc. 13(Suppl 2):S3. http://dx.doi.org/10.1186/1758-2652-13-S2-S3.
18. Fader LD, Malenfant E, Parisien M, Carson R, Bilodeau F, Landry S, Pesant M, Brochu C, Morin S, Chabot C, Halmos T, Bousquet Y, Bailey MD, Kawai SH, Coulombe R, LaPlante S, Jakalian A, Bhardwaj PK, Wernic D, Schroeder P, Amad M, Edwards P, Garneau M, Duan J, Cordingley M, Bethell R, Mason SW, Bös M, Bonneau P, Poupart M-A, Faucher A-M, Simoneau B, Fenwick C, Yoakim C, Tsantrizos Y. 2014. Discovery of BI 224436, a noncatalytic site integrase inhibitor (NCINI) of HIV-1 ACS Med. Chem. Lett. 5:422-427. http://dx.doi.org/10.1021/ ml500002n.
19. Tsantrizos YS, Boes M, Brochu C, Fenwick C, Malenfant E, Mason S, Pesant M, Boehringer Ingelheim Pharma. November 2007. Inhibitors of human immunodeficiency virus replication. Patent WO/2007/131350.
20. Cherepanov P, Sun ZY, Rahman S, Maertens G, Wagner G, Engelman A. 2005. Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75. Nat. Struct. Mol. Biol. 12:526-532. http://dx.doi.org/10.1038/nsmb937.
21. Hou Y, McGuinness DE, Prongay AJ, Feld B, Ingravallo P, Ogert RA, Lunn CA, 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. http://dx.doi.org/10.1177/ 1087057108317060.
22. 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. 2010. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat. Chem. Biol. 6:442-448. http://dx.doi.org/10.1038/nchembio.370.
23. De Luca L, Barreca ML, Ferro S, Christ F, Iraci N, Gitto R, Monforte AM, Debyser Z, Chimirri A. 2009. Pharmacophore-based discovery of small-molecule inhibitors of protein-protein interactions between HIV-1 integrase and cellular cofactor LEDGF/p75. Chem. Med. Chem. 4:1311-1316. http://dx.doi.org/10.1002/ cmdc.200900070.
24. Tsantrizos YS, Bailey MD, Bilodeau F, Carson RJ, Coulombe R, Fader L, Halmos T, Kawai S, Landry S, Laplante S, Morin S, Parisien M, Poupart M-A, Simoneau B. 2009. Inhibitors of human immunodeficiency virus replication. Patent application WO 2009/062285.
25. Taganov KD, Cuesta I, Daniel R, Cirillo LA, Katz RA, Zaret KS, Skalka AM. 2004. Integrase-specific enhancement and suppression of retroviral DNA integration by compacted chromatin structure in vitro. J. Virol. 78: 5848-5855. http://dx.doi.org/10.1128/JVI.78.11.5848-5855.2004.
26. Hawkins ME, Pfleiderer W, Mazumder A, Pommier YG, Balis FM. 1995. Incorporation of a fluorescent guanosine analog into oligonucleotides and its application to a real time assay for the HIV-1 integrase 3- processing reaction. Nucleic Acids Res. 23:2872-2880. http://dx.doi.org/10.1093/nar/23.15.2872.
27. Zhou G, Cummings R, Hermes J, Moller DE. 2001. Use of homogeneous time-resolved fluorescence energy transfer in the measurement of nuclear receptor activation. Methods 25:54-61. http://dx.doi.org/10.1006/meth.2001.1215.
28. Shaw GM, Hahn BH, Arya SK, Groopman JE, Gallo RC, Wong-Staal F. 1984. Molecular characterization of human T-cell leukemia (lymphotrophic) virus type III in the acquired immune deficiency syndrome. Science 226:1165-1170. http://dx.doi.org/10.1126/science.6095449.
29. Adachi A, Gendelman HE, Koenig S, Folks T, Willey R, Rabson A, Martin MA. 1986. Production of acquired immunodeficiency syndromeassociated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J. Virol. 59:284-291.
30. Johnson VA, Byington RE. 1990. Quantitative assays for virus infectivity: infectivity assay (virus yield assay), p 71-76. In Aldovini A, Walker BD (ed), Techniques in HIV research. Stockton Press, New York, NY.
31. Schmidt NJ, Emmons RW. 1989. General principles of laboratory diagnostic methods for viral, rickettsial and chlamydial infections, p 1-35. In Schmidt NJ, Emmons RW (ed), Diagnostic procedures for rickettsial and chlamydial infections, 6th ed. American Public Health Association, Washington, DC.
32. Mosmann T. 1983. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 65:55-63. http://dx.doi.org/10.1016/0022-1759(83)90303-4.
33. Lemke CT, Titolo S, von Schwedler U, Goudreau N, Mercier JF, Wardrop E, Faucher AM, Coulombe R, Banik SS, Fader L, Gagnon A, Kawai SH, Rancourt J, Tremblay M, Yoakim C, Simoneau B, Archambault J, Sundquist WI, Mason SW. 2012. Distinct effects of two HIV-1 capsid assembly inhibitor families that bind the same site within the Nterminal domain of the viral CA protein. J. Virol. 86:6643-6655. http://dx.doi.org/10.1128/JVI.00493-12.
34. Jegede O, Babu J, di Santo R, McColl DJ, Weber J, Quiñones-Mateu ME. 2008. HIV type 1 integrase inhibitors: from basic research to clinical implications. AIDS Rev. 10:172-189.
35. O'Meara JA, Yoakim C, Bonneau PR, Bös M, Cordingley MG, Déziel R, Doyon L, Duan J, Garneau M, Guse I, Landry S, Malenfant E, Naud J, Ogilvie WW, Thavonekham B, Simoneau B. 2005. Novel 8-substituted dipyridodiazepinone inhibitors with a broad spectrum of activity against HIV-1 strains resistant to non-nucleoside reverse transcriptase inhibitors. J. Med. Chem. 48:5580-5588. http://dx.doi.org/10.1021/jm050255t.
36. Doyon LD, Croteau G, Thibeault D, Poulin F, Pilote L, Lamarre D. 1996. Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors. J. Virol. 70:3763-3769.
37. Rajotte D, Tremblay S, Pelletier A, Salois P, Bourgon L, Coulombe R, Mason S, Lamorte L, Sturino CF, Bethell R. 2013. Identification and characterization of a novel HIV-1 nucleotide-competing reverse transcriptase inhibitor series. Antimicrob. Agents Chemother. 57:2712-2718. http://dx.doi.org/10.1128/AAC.00113-13.
38. Prichard MN, Shipman C. 1990. A three-dimensional model to analyze drug-drug interactions. Antiviral Res. 14:181-206. http://dx.doi.org/10.1016/ 0166-3542(90)90001-N.
39. Prichard MN, Prichard LE, Baguley WA, Nassiri MR, Shipman C. 1991. Three-dimensional analysis of the synergistic cytotoxicity of ganciclovir and zidovudine. Antimicrob. Agents Chemother. 35:1060-1065. http://dx.doi.org/10. 1128/AAC.35.6.1060.
40. White PW, Llinàs-Brunet M, Amad M, Bethell RC, Bolger G, Cordingley MG, Duan J, Garneau M, Lagacé L, Thibeault D, Kukolj G. 2010. Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease. Antimicrob. Agents Chemother. 54:4611-4618. http://dx.doi.org/10.1128/AAC.00787-10.
41. Beaulieu PL, Bös M, Cordingley MG, Chabot C, Fazal G, Garneau M, Gillard JR, Jolicoeur E, LaPlante S, McKercher G, Poirier M, Poupart M-A, Tsantrizos YS, Duan J, Kukolj G. 2012. Discovery of the first thumb pocket 1 NS5B polymerase inhibitor (BILB 1941) with demonstrated antiviral activity in patients chronically infected with genotype 1 hepatitis C virus (HCV). J. Med. Chem. 55:7650-7666. http://dx.doi.org/10.1021/jm3006788.
42. Cotelle P. 2009. New hexahydrodiazocinonaphthyridine triones as HIV-1 integrase inhibitors: WO2008048538 A1. Expert Opin. Ther. Pat. 19:87-93. http://dx.doi.org/10.1517/13543770802603577.
43. Jurado KA, Wang H, Slaughter A, Feng L, Kessl JJ, Koh Y, Wang W, Ballandras-Colas A, Patel PA, Fuchs JR, Kvaratskhelia M, Engelman A. 2013. Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation. Proc. Natl. Acad. Sci. U. S. A. 110:8690-8695. http://dx.doi.org/10.1073/pnas.1300703110.
44. Christ F, Shaw S, Demeulemeester J, Desimmie BA, Marchand A, Butler S, Smets W, Chaltin P, Westby M, Debyser Z, Pickford C. 2012. Small-molecule inhibitors of the LEDGF/p75 binding site of integrase block HIV replication and modulate integrase multimerization. Antimicrob. Agents Chemother. 56:4365-4374. http://dx.doi.org/10.1128/AAC.00717-12.
45. Tsiang M, Jones GS, Niedziela-Majka A, Kan E, Lansdon EB, Huang W, Hung M, Samuel D, Novikov N, Xu Y, Mitchell M, Guo H, Babaoglu K, Liu X, Geleziunas R, Sakowicz R. 2012. New class of HIV-1 integrase (IN) inhibitors with a dual mode of action. J. Biol. Chem. 287:21189-21203. http://dx.doi.org/10.1074/jbc. M112.347534.
46. Kessl JJ, Jena N, Koh Y, Taskent-Sezgin H, Slaughter A, Feng L, de Silva S, Wu L, Le Grice SF, Engelman A, Fuchs JR, Kvaratskhelia M. 2012. Multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors. J. Biol. Chem. 287:16801-16811. http://dx.doi.org/10.1074/jbc.M112.354373.
47. Engelman A, Kessl JJ, Kvaratskhelia M. 2013. Allosteric inhibition of HIV-1 integrase activity. Curr. Opin. Chem. Biol. 17:339-345. http://dx.doi.org/10.1016/j.cbpa.2013.04.010.
48. Molla A, Vasavanonda S, Kumar G, Sham HL, Johnson M, Grabowski B, Denissen JF, Kohlbrenner W, Plattner JJ, Leonard JM, Norbeck DW, Kempf DJ. 1998. Human serum attenuates the activity of protease inhibitors toward wild-type and mutant human immunodeficiency virus. Virology 250:255-262. http://dx.doi.org/ 10.1006/viro.1998.9383.
49. Dudley MN, Blaser J, Gilbert D, Zinner SH. 1990. Significance of extravascular protein binding for antimicrobial pharmacodynamics in an in vitro capillary model of infection. Antimicrob. Agents Chemother. 34: 98-101. http://dx.doi.org/10.1128/AAC.34.1.98.
50. Balakrishnan M, Yant SR, Tsai L, O'Sullivan C, Bam RA, Tsai A, Niedziela-Majka A, Stray KM, Sakowicz R, Cihlar T. 2013. Non-catalytic site HIV-1 integrase inhibitors disrupt core maturation and induce a reverse transcription block in target cells. PLoS One 8:e74163. http://dx.doi.org/10. 1371/journal.pone.0074163.
51. Bieniasz PD, Fridell RA, Aramori I, Ferguson SS, Caron MG, Cullen BR. 1997. HIV-1-induced cell fusion is mediated by multiple regions within both the viral envelope and the CCR-5 co-receptor. EMBO J. 16: 2599-2609. http://dx.doi.org/10.1093/emboj/16.10.2599.
52. Shen L, Peterson S, Sedaghat AR, McMahon MA, Callender M, Zhang H, Zhou Y, Pitt E, Anderson KS, Acosta EP, Siliciano RF. 2008. Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs. Nat. Med. 14:762-766. http://dx.doi.org/10.1038/nm1777.
53. Desimmie BA, Schrijvers R, Demeulemeester J, Borrenberghs D, Weydert C, Thys W, Vets S, Van Remoortel B, Hofkens J, De Rijck J, Hendrix J, Bannert N, Gijsbers R, Christ F, Debyser Z. 2013. LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions. Retrovirology 10:57. http://dx.doi.org/10.1186/1742-4690-10-57.
54. Trainor GL. 2007. The importance of plasma protein binding in drug discovery. Expert Opin. Drug Discov. 2:51-64. http://dx.doi.org/10.1517/ 17460441.2.1.51.
55. Moyle G, Gatell J, Perno CF, Ratanasuwan W, Schechter M, Tsoukas C. 2008. Potential for new antiretrovirals to address unmet needs in the management of HIV-1 infection. AIDS Patient Care STDS 22:459-471. http://dx.doi.org/10.1089/ apc.2007.0136.