LEDGINs, non-catalytic site inhibitors of HIV-1 integrase: A patent review (2006-2014)

Expert Opinion on Therapeutic Patents

Volumn 24, Issue 6, 2014, Pages 609-632

  Demeulemeester, Jonas ^a,b   Chaltin, Patrick ^c   Marchand, Arnaud ^c   De Maeyer, Marc ^a   Debyser, Zeger ^b   Christ, Frauke ^b  

^a UNIVERSITY OF LEUVEN   (Belgium)

^b DEPARTMENT OF PHARMACEUTICAL AND PHARMACOLOGICAL SCIENCES   (Belgium)

^c Centre for Innovation and Stimulation of Medicines Development   (Belgium)

Author keywords

AIDS; Allosteric; Combination antiretroviral therapy; HIV; Integrase; LEDGIN; Lens epithelium derived growth factor p75; Maturation; Non catalytic site integrase inhibitor

Indexed keywords

2 (QUINOLIN 3 YL)ACETIC ACID; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; INTEGRASE; LENS EPITHELIUM DERIVED GROWTH FACTOR; UNCLASSIFIED DRUG; INTEGRASE INHIBITOR;

DRUG DESIGN; DRUG INDUSTRY; DRUG MECHANISM; DRUG SCREENING; HIGH THROUGHPUT SCREENING; HUMAN; IC 50; NONHUMAN; REVIEW; DRUG DEVELOPMENT; PATENT;

DRUG DISCOVERY; HIGH-THROUGHPUT SCREENING ASSAYS; HIV INTEGRASE INHIBITORS; PATENTS AS TOPIC;

EID: 84901287873     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1517/13543776.2014.898753     Document Type: Review

References (125)

1. UNAIDS report on the global AIDS epidemic 2012 [Internet]. UNAIDS JUNPOHA. 2012.Available from: Http://www.unaids. org/en/media/unaids/ contentassets/ documents/epidemiology/2012/gr2012/ 20121120-UNAIDS-Global- Report-2012-en.pdf [Last accessed 21 Aug 2013]
2. Engelman A, Cherepanov P. The structural biology of HIV-1: Mechanistic and therapeutic insights. Nat Rev Microbiol 2012;10(4):279-90
3. Cherepanov P, Maertens GN, Hare S. Structural insights into the retroviral DNA integration apparatus. Curr Opin Struct Biol 2011;21(2):249-56
4. U.S. Food and Drug Administration. 2013.Available from: Http://www.fda.gov [Last accessed 21 Aug 2013]
5. Christ F, Voet A, Marchand A, et al. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat Chem Biol 2010;6(6):442-8
6. Fenwick C, Bethell R, Bonneau P, et al. Identification of BI-C, a novel HIV-1 non-catalytic site integrase inhibitor. 18th Conference on Retroviruses and Opportunistic Infections; 27 February-2 March 2011; Boston, MA, USA
7. Jaskolski M, Alexandratos JN, Bujacz G, Wlodawer A. Piecing together the structure of retroviral integrase, an important target in AIDS therapy. FEBS J 2009;276(11):2926-46
8. Li X, Krishnan L, Cherepanov P, Engelman A. Structural biology of retroviral DNA integration. Virology 2011;411(2):194-205
9. Nowotny M. Retroviral integrase superfamily: The structural perspective. EMBO Rep 2009;10(2):144-51
10. Hare S, Gupta SS, Valkov E, et al. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 2010;464(7286):232-6
11. FDA Isentress (raltegravir) new drug application (NDA) approval letter. Food and Drug Administration Rockville, MD 20857. 2007. Available from: Http://www.accessdata.fda.gov/ drugsatfda-docs/appletter/2007/ 022145s000tr.pdf [Last accessed 17 Dec 2013]
12. FDA Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) new drug application (NDA) approval letter [Internet]. Food and Drug Administration Silver Spring MD 20993. Available from: Http://www.accessdata. fda.gov/drugsatfda-docs/appletter/2012/ 0203100Orig1s000ltr.pdf [cited 2013 Dec 17]
13. FDA Tivicay (dolutegravir) new drug application (NDA) approval letter [Internet]. Food and Drug Administration Silver Spring MD 20993. 2013;Available from: Http://www. accessdata.fda.gov/drugsatfda-docs/ appletter/2013/ 204790Orig1s000ltr.pdf [Last accessed 17 Dec 2013]
14. Hazuda DJ, Felock P, Witmer M, et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000;287(5453):646-50 (Pubitemid 30070911
15. Demeulemeester J, De Maeyer M, Debyser Z. HIV-1 integrase drug discovery comes of age. Topics in medicinal chemistry. Springer, Berlin Heidelberg; 2014. p. 1-52
16. Johnson VA, Calvez V, Günthard HF, et al. Update of the drug resistance mutations in HIV-1: March 2013. Top Antivir Med 2013;21(1):6-14
17. Wainberg MA, Mesplède T, Quashie PK. The development of novel HIV integrase inhibitors and the problem of drug resistance. Curr Opin Virol 2012;2(5):656-62
18. Al-Mawsawi LQ, Neamati N. Allosteric inhibitor development targeting HIV-1 integrase. ChemMedChem 2011;6(2):228-41
19. Voet AR, Maeyer MD, Debyser Z, Christ F. In search of second-generation HIV integrase inhibitors: Targeting integration beyond strand transfer. Future Med Chem 2009;1(7):1259-74
20. Demeulemeester J, Christ F, De Maeyer M, Debyser Z. Fueling HIV-1 integrase drug design with structural insights. Drug Discov Today Technol 2012;9(3):e175-226
21. Engelman A, Kessl JJ, Kvaratskhelia M. Allosteric inhibition of HIV-1 integrase activity. Curr Opin Chem Biol 2013;17(3):339-45
22. Christ F, Debyser Z. The LEDGF/ p75 integrase interaction, a novel target for anti-HIV therapy. Virology 2013;435(1):102-9
23. Kessl JJ, Jena N, Koh Y, et al. Multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem 2012;287(20):16801-11
24. 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(22):6723-9 (Pubitemid 28521805
25. Eidahl JO, Crowe BL, North JA, et al. Structural basis for high-Affinity binding of LEDGF PWWP to mononucleosomes. Nucleic Acids Res 2013;41(6):3924-36
26. van Nuland R, van Schaik FM, Simonis M, et al. Nucleosomal DNA binding drives the recognition of H3K36-methylated nucleosomes by the PSIP1-PWWP domain. Epigenetics Chromatin 2013;6(1):12
27. 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(4):760-73 (Pubitemid 43993915
28. 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(32):33421-9 (Pubitemid 39062991
29. Tsutsui KM, Sano K, Hosoya O, et al. Nuclear protein LEDGF/p75 recognizes supercoiled DNA by a novel DNAbinding domain. Nucleic Acids Res 2011;39(12):5067-81
30. De Rijck J, Bartholomeeusen K, Ceulemans H, et al. High-resolution profiling of the LEDGF/p75 chromatin interaction in the ENCODE region. Nucleic Acids Res 2010;38(18):6135-47
31. Cherepanov P, Sun Z-YJ, Rahman S, et al. Solution structure of the HIV-1 integrase-binding domain in LEDGF/ p75. Nat Struct Mol Biol 2005;12(6):526-32 (Pubitemid 43085883
32. Cherepanov P, Devroe E, Silver PA, Engelman A. 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(47):48883-92 (Pubitemid 39625769
33. Schrijvers R, De Rijck J, Demeulemeester J, et al. LEDGF/p75-independent HIV-1 replication demonstrates a role for HRP-2 and remains sensitive to inhibition by LEDGINs. PLoS Pathog 2012;8(3):e1002558
34. Wang H, Jurado KA, Wu X, et al. HRP2 determines the efficiency and specificity of HIV-1 integration in LEDGF/p75 knockout cells but does not contribute to the antiviral activity of a potent LEDGF/p75-binding site integrase inhibitor. Nucleic Acids Res 2012;40(22):11518-30
35. Ciuffi A, Llano M, Poeschla E, et al. A role for LEDGF/p75 in targeting HIV DNA integration. Nat Med 2005;11(12):1287-9 (Pubitemid 41752906
36. Shun M-C, 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(14):1767-78 (Pubitemid 47076476
37. 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(1):372-81 (Pubitemid 36043586
38. Raghavendra NK, Engelman A. 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 2007;360(1):1-5
39. Llano M, Delgado S, Vanegas M, Poeschla EM. Lens epithelium-derived growth factor/p75 prevents proteasomal degradation of HIV-1 integrase. J Biol Chem 2004;279(53):55570-7 (Pubitemid 40066560
40. 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(35):33528-39 (Pubitemid 37055807
41. 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(23):11498-509 (Pubitemid 44788865
42. Debyser Z, Cherepanov P, De Clercq E. Integrase cofactor. WO04029246; 2004
43. Legrain P, Rain J-C, Benarous R, et al. Protein-protein interactions in human immunodeficiency virus. WO03046176; 2003
44. Debyser Z, Cherepanov P, De Clercq E. Integrase cofactor. US7514233; 2009
45. Debyser Z, Cherepanov P, De Clercq E. Integrase cofactor. EP1546331; 2012
46. Cherepanov P, Ambrosio ALB, Rahman S, et al. Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc Natl Acad Sci USA 2005;102(48):17308-13 (Pubitemid 41740862
47. Hayouka Z, Rosenbluh J, Levin A, et al. Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium. Proc Natl Acad Sci USA 2007;104(20):8316-21 (Pubitemid 47175485
48. 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(5):406-14 (Pubitemid 351793981
49. 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(1):139-44
50. De Luca L, Barreca ML, Ferro S, et al. Pharmacophore-based discovery of smallmolecule inhibitors of protein-protein interactions between HIV-1 integrase and cellular cofactor LEDGF/p75. ChemMedChem 2009;4(8):1311-16
51. Fan X, Zhang F-H, Al-Safi RI, et al. Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: A scaffold hopping approach using salicylate and catechol groups. Bioorg Med Chem 2011;19(16):4935-52
52. De Luca L, Ferro S, Gitto R, et al. Small molecules targeting the interaction between HIV-1 integrase and LEDGF/ p75 cofactor. Bioorg Med Chem 2010;18(21):7515-21
53. Peat TS, Rhodes DI, Vandegraaff N, et al. Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design. PLoS One 2012;7(7):e40147
54. Christ F, Shaw S, Demeulemeester J, et al. Small-molecule inhibitors of the LEDGF/p75 binding site of integrase block HIV replication and modulate integrase multimerization. Antimicrob Agents Chemother 2012;56(8):4365-74
55. Fenwick CW, Tremblay S, Wardrop E, et al. Resistance studies with HIV-1 noncatalytic site integrase inhibitors. 16 ed. International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies; 7-11 June 2011; Los Cabos, Mexico
56. Aslanyan S, Ballow C, Sabo J. Safety and pharmacokinetics (PK) of single rising oral doses of a novel HIV integrase inhibitor in healthy volunteers. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 17-20 September 2011; Chicago, IL, USA
57. Boehringer Ingelheim and Gilead sign license agreement for novel HIV noncatalytic integrase inhibitors. 2011.Boehringer Ingelheim. Available from: Http://www.boehringer-ingelheim. com/news/news-releases/press-releases/ 2011/06-october-2011-gilead.html [Last accessed 2013 Aug 27]
58. Tsiang M, Jones GS, Niedziela-Majka A, et al. New class of HIV-1 integrase (IN) inhibitors with a dual mode of action. J Biol Chem 2012;287(25):21189-203
59. Tsantrizos YS, Boes M, Brochu C, et al. Inhibitors of human immunodeficiency virus replication. WO07131350; 2007
60. Tsantrizos YS, Bailey MD, Bilodeau F, et al. Inhibitors of human immunodeficiency virus replication. WO09062285; 2009
61. Michel P, Ley SV. Synthesis of enantiomers of butane-1,2- diacetalprotected glyceraldehyde and of (R, R)-butane-1,2-diacetal-protected glycolic acid. Synthesis 2003;35(10):1598-602 (Pubitemid 36928523
62. Sharpless KB, Amberg W, Bennani YL, et al. The osmium-catalyzed asymmetric dihydroxylation: A new ligand class and a process improvement. J Org Chem 1992;57(10):2768-71
63. Carson R, Fader L, Kawai S, et al. Inhibitors of human immunodeficiency virus replication. WO09062288; 2009
64. Tsantrizos YS, Bailey MD, Bilodeau F, et al. Inhibitors of human immunodeficiency virus replication. WO09062289; 2009
65. Tsantrizos YS, Bailey MD, Bhardwaj N, et al. Inhibitors of human immunodeficiency virus replication. WO09062308; 2009
66. Yoakim C, Bailey MD, Bilodeau F, et al. Inhibitors of human immunodeficiency virus replication. WO10130034; 2010
67. Bardiot D, Chaltin P, Christ F, et al. Thieno [2, 3-B] pyridine derivatives as viral replication inhibitors. WO10130842; 2010
68. Pauwels R, Balzarini J, Baba M, et al. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Methods 1988;20(4):309-21
69. Chaltin P, Debyser Z, De Maeyer M, et al. Novel viral replication Inhibitors. WO11015641; 2011
70. Carlens G, Chaltin P, Christ F, et al. Novel antiviral compounds. WO11076765; 2011
71. Chaltin P, Christ F, Debyser Z, et al. Novel antiviral compounds. WO12065963; 2012
72. KU Leuven enters into license agreement with Pfizer. KU Leuven R&D. 2010.Available from: Https://lrd.kuleuven. be/en/news/kuleuven-enters-into- licenseagreement-with-pfizer [Last accessed 27 Aug 2013]
73. Bell AS, Gardner IB, Pryde DC, et al. Inhibitors of HIV replication. WO12066442; 2012
74. Llano M, Saenz DT, Meehan A, et al. An essential role for LEDGF/p75 in HIV integration. Science 2006;314(5798):461-4 (Pubitemid 44628966
75. Babaoglu K, Bjornson K, Guo H, et al. 2-quinolinyl-Acetic acid derivatives as HIV antiviral compounds. WO12003498; 2012
76. Babaoglu K, Bjornson K, Guo H, et al. Napht-2-ylacetic acid derivatives to treat aids. WO12003497; 2012
77. Li W, De Croos P, Fandrick KR, et al. Process for the preparation of an HIV integrase inhibitor. WO12138670; 2012
78. Chen Y-C, Wu T-F, Deng J-G, et al. Multiple dendritic catalysts for asymmetric transfer hydrogenation. J Org Chem 2002;67(15):5301-6 (Pubitemid 34793200
79. Tang W, Capacci AG, Wei X, et al. A general and special catalyst for Suzuki-Miyaura coupling processes. Angew Chem Int Ed Engl 2010;49(34):5879-83
80. Tang W, Keshipeddy S, Zhang Y, et al. Efficient monophosphorus ligands for palladium-catalyzed Miyaura borylation. Org Lett 2011;13(6):1366-9
81. Li ZJ, Li Z, Luo L, et al. Solid state forms of HIV inhibitor. WO12138669; 2012
82. Mitchell ML, Roethle PA, Xu L, et al. Benzothiazole compounds and their pharmaceutical use. WO12145728; 2012
83. Babaoglu K, Bjornson KL, Hrvatin P, et al. 2-(tert-butoxy)-2-(7- methylquinolin-6-yl) acetic acid derivatives for treating aids. WO13103724; 2013
84. Babaoglu K, Brizgys G, Guo H, et al. Napthalene acetic acid derivatives against HIV infection. WO13103738; 2013
85. Babaoglu K, Brizgys G, Cha J, et al. Benzothiazol-6-yl acetic acid derivatives and their use for treating an HIV infection. WO13159064; 2013
86. Pendri A, Li G, Gerritz S, et al. Inhibitors of human immunodeficiency virus replication. WO12033735; 2012
87. Naidu BN, Patel M. Inhibitors of human immunodeficiency virus replication. WO13025584; 2013
88. Zheng ZB, D'Andrea S, Langley DR, Naidu BN. Inhibitors of human immunodeficiency virus replication. WO13134142; 2013
89. Pendri A, Langley DR, Gerritz S, et al. Fused pyrimidines as inhibitors of immunodeficiency virus replication. WO13134113; 2013
90. Walker MA, Sorenson ME, Naidu BN, et al. Inhibitors of human immunodeficiency virus replication. WO13123148; 2013
91. De La Rosa MA, Haydar SN, Johns BA, Velthuisen EJ. Isoquinoline compounds and methods for treating HIV. WO12102985; 2012
92. De La Rosa MA, Johns BA, Samano V, et al. Azaindole compounds and methods for treating HIV. WO13012649; 2013
93. Haydar SN, Johns BA, Velthuisen EJ. Pyrrolopyridinone compounds and methods for treating HIV. WO13043553; 2013
94. De La Rosa MA, Johns BA, Kazmierski WM, et al. Compounds and methods for treating HIV. WO14009794; 2014
95. Hattori K, Kurihara N, Iwaki T, et al. HIV replication inhibitor. WO13002357; 2013
96. Iwaki T, Tomita K. HIV replication inhibitor. WO13062028; 2013
97. Sugiyama S, Akiyama T, Taoda Y. HIV replication inhibitor. WO1315762; 2013
98. Chasset S, Chevreuil F, Ledoussal B, et al. Inhibitors of viral replication, their process of preparation and their therapeutical uses. WO12137181; 2012
99. Chasset S, Chevreuil F, Ledoussal B, et al. Inhibitors of viral replication, their process of preparation and their therapeutical uses. WO12140243; 2012
100. Son JC, Kim BJ, Kim JH, et al. Novel antiviral pyrrolopyridine derivative and a production method for same. WO13073875; 2013
101. Rhodes DI, Peat TS, Vandegraaff N, et al. Crystal structures of novel allosteric peptide inhibitors of HIV integrase identify new interactions at the LEDGF binding site. ChemBioChem 2011;12(15):2311-15
102. Serrao E, Debnath B, Otake H, et al. Fragment-based discovery of 8-hydroxyquinoline inhibitors of the HIV-1 integrase-lens epithelium-derived growth factor/p75 (IN-LEDGF/p75) interaction. J Med Chem 2013;56(6):2311-22
103. Hu G, Li X, Zhang X, et al. Discovery of inhibitors to block interactions of HIV-1 integrase with human LEDGF/ p75 via structure-based virtual screening and bioassays. J Med Chem 2012;55(22):10108-17
104. Sanchez TW, Debnath B, Christ F, et al. Discovery of novel inhibitors of LEDGF/ p75-IN protein-protein interactions. Bioorg Med Chem 2013;21(4):957-63
105. Rhodes DI, Peat TS, Vandegraaff N, et al. Structural basis for a new mechanism of inhibition of HIV-1 integrase identified by fragment screening and structure-based design. Antivir Chem Chemother 2011;21(4):155-68
106. Jurado KA, Wang H, Slaughter A, et al. Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation. Proc Natl Acad Sci USA 2013;110(21):8690-5
107. Feng L, Sharma A, Slaughter A, et al. The A128T resistance mutation reveals aberrant protein multimerization as the primary mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem 2013;288(22):15813-20
108. Kessl JJ, Li M, Ignatov M, et al. FRET analysis reveals distinct conformations of IN tetramers in the presence of viral DNA or LEDGF/p75. Nucleic Acids Res 2011;39(20):9009-22
109. McKee CJ, Kessl JJ, Shkriabai N, et al. Dynamic modulation of HIV-1 integrase structure and function by cellular lens epithelium-derived growth factor (LEDGF) protein. J Biol Chem 2008;283(46):31802-12
110. Schrijvers R, Demeulemeester J, De Rijck J, et al. Characterization of rare lens epithelium-derived growth factor/ p75 genetic variants identified in HIV-1 long-Term nonprogressors. AIDS 2013;27(4):539-43
111. Le Rouzic E, Bonnard D, Chasset S, et al. Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the postintegration stage. Retrovirology 2013;10(1):144
112. Demeulemeester J, Tintori C, Botta M, et al. Development of an AlphaScreenbased HIV-1 integrase dimerization assay for discovery of novel allosteric inhibitors. J Biomol Screen 2012;17(5):618-28
113. Tsiang M, Jones GS, Hung M, et al. Dithiothreitol causes HIV-1 integrase dimer dissociation while agents interacting with the integrase dimer interface promote dimer formation. Biochemistry 2011;50(10):1567-81
114. Engelman A, Englund G, Orenstein JM, et al. Multiple effects of mutations in human immunodeficiency virus type 1 integrase on viral replication. J Virol 1995;69(5):2729-36
115. Desimmie BA, Schrijvers R, Demeulemeester J, et al. LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions. Retrovirology 2013;10:57
116. Balakrishnan M, Yant SR, Tsai L, et al. Non-catalytic site HIV-1 integrase inhibitors disrupt core maturation and induce a reverse transcription block in target cells. PLoS One 2013;8(9):e74163
117. Jurado KA, Engelman A. Multimodal mechanism of action of allosteric HIV-1 integrase inhibitors. Expert Rev Mol Med 2013;15:e14
118. Shen L, Rabi SA, Sedaghat AR, et al. A critical subset model provides a conceptual basis for the high antiviral activity of major HIV drugs. Sci Transl Med 2011;3(91):91-63
119. Fenwick C, Bethell R, Cordingley M. BI 224436, a non-catalytic site integrase inhibitor, is a potent inhibitor of the replication of treatment-naive and raltegravir-resistant clinical isolates of HIV-1. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 17-20 September 2011; Chicago, IL, USA
120. Messiaen P, Wensing AMJ, Fun A, et al. Clinical use of HIV integrase inhibitors: A systematic review and meta-Analysis. PLoS One 2013;8(1):e52562
121. Eron JJ, Clotet B, Durant J, et al. Safety and efficacy of dolutegravir in treatmentexperienced subjects with raltegravirresistant HIV type 1 infection: 24-week results of the VIKING Study. J Infect Dis 2013;207(5):740-8
122. Nichols G, Mills A, Grossberg R, et al. Antiviral activity of dolutegravir in subjects with failure on an integrase inhibitor-based regimen: Week 24 phase 3 results from VIKING-3. J Int AIDS Soc 2012;15(Suppl 4):18112
123. Yoakim C, Amad M, Bailey M. Preclinical profile of BI 224436, a novel HIV-1 non-catalytic site integrase inhibitor. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 17-20 September 2011; Chicago, IL, USA
124. Brown A, McSharry J, Kulawy R. Pharmacodynamics of BI 224436 for HIV-1 in an in vitro hollow fiber infection model system. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 17-20 September 2011; Chicago, IL, USA
125. Fader LD, Malenfant E, Parisien M, et al. Discovery of BI 224436, a noncatalytic site integrase inhibitor (NCINI) of HIV-1. ACS Med Chem Lett 2014