Abstract
Insertion of the viral genome into host cell chromatin is a pivotal step in the replication cycle of the human immunodeficiency virus and other retroviruses. Blocking the viral integrase enzyme that catalyzes this reaction therefore provides an attractive therapeutic strategy. Nevertheless, many years lie between the initial discovery of integrase and the clinical approval of the first integrase strand transfer inhibitor, raltegravir, in 2007. Recently, elvitegravir was second to make it into the clinic, while dolutegravir, a second-generation integrase inhibitor, is close to receiving the green light as well. Viral resistance and cross-resistance among these strand transfer inhibitors however warrant the search for compounds targeting HIV integration through different mechanisms of action. The most advanced class of allosteric integrase inhibitors, coined LEDGINs or non-catalytic integrase inhibitors (NCINIs), has shown remarkable antiviral activity that extends beyond the viral integration step. Time will tell however if they will stand the test of clinical development. Notably, the development of LEDGINs and other integrase inhibitors is aided by recent structural and mechanistic insights into the retroviral integration apparatus. Here we provide an overview of the development of integrase strand transfer and allosteric inhibitors while exploring their mechanisms of action and patterns of viral resistance.
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Abbreviations
- 1-LTR:
-
1-Long terminal repeat
- 2-LTR:
-
2-Long terminal repeats
- 3P:
-
3′-Processing
- ADME:
-
Absorption distribution, metabolism, and excretion
- AIDS:
-
Acquired immunodeficiency syndrome
- ALLINI:
-
Allosteric integrase inhibitor
- ART:
-
Antiretroviral therapy
- ARV:
-
Antiretroviral
- CC50 :
-
50% cytotoxic concentration
- CCD:
-
Catalytic core domain
- CCR5:
-
C–C chemokine receptor 5
- CR:
-
Charged region
- CTD:
-
C-terminal domain
- DKA:
-
Diketo acid
- DNA:
-
Deoxyribonucleic acid
- EC50 :
-
50% Effective concentration
- FDA:
-
Food and Drug Administration
- HAART:
-
Highly active antiretroviral therapy
- HCV:
-
Hepatitis C virus
- HDGF:
-
Hepatoma-derived growth factor
- HIV-1:
-
Human immunodeficiency virus type 1
- HIV-2:
-
Human immunodeficiency virus type 2
- HRP-2:
-
Hepatoma-derived growth factor-related protein 2
- HSAB:
-
Hard and soft Lewis acids and bases
- IBD:
-
Integrase-binding domain
- IC50 :
-
50% inhibitory concentration
- IN:
-
Integrase
- INI:
-
Integrase inhibitor
- IRBM:
-
Instituto di Ricerche di Biologia Moleculare
- LEDGF/p75:
-
Lens epithelium-derived growth factor/p75
- LTR:
-
Long terminal repeat
- MACCS:
-
Molecular access system
- mRNA:
-
Messenger ribonucleic acid
- MTT:
-
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- NCINI:
-
Non-catalytic site integrase inhibitor
- NLS:
-
Nuclear localization signal
- NMR:
-
Nuclear magnetic resonance
- NNRTI:
-
Non-nucleoside reverse transcriptase inhibitor
- NRTI:
-
Nucleoside reverse transcriptase inhibitor
- NTD:
-
N-terminal domain
- PAEC50 :
-
Protein-adjusted 50% effective concentration
- PAIC50 :
-
Protein-adjusted 50% inhibitory concentration
- PFV:
-
Prototype foamy virus
- PHAT:
-
Pseudo-HEAT analogous topology
- PIC:
-
Pre-integration complex
- PK:
-
Pharmacokinetic
- PPI:
-
Protein–protein interaction
- PR:
-
Protease
- PrEP:
-
Preexposure prophylaxis
- PWWP:
-
Pro–Trp–Trp–Pro domain
- RNA:
-
Ribonucleic acid
- RT:
-
Reverse transcriptase
- SAR:
-
Structure–activity relationship
- SIV:
-
Simian immunodeficiency virus
- SPR:
-
Surface plasmon resonance
- ST:
-
Strand transfer
- STD-NMR:
-
Saturation transfer difference nuclear magnetic resonance
- tDNA:
-
Target deoxyribonucleic acid
- TRN-SR2:
-
Transportin-SR2
- vDNA:
-
Viral deoxyribonucleic acid
- WT:
-
Wild type
References
Heeney JL, Dalgleish AG, Weiss RA (2006) Origins of HIV and the evolution of resistance to AIDS. Science 313:462–466
Centers for Disease Control (CDC) (1981) Pneumocystis pneumonia–Los Angeles. MMWR Morb Mortal Wkly Rep 30:250–252
Centers for Disease Control (CDC) (1981) Kaposi’s sarcoma and Pneumocystis pneumonia among homosexual men–New York City and California. MMWR Morb Mortal Wkly Rep 30:305–308
Barré-Sinoussi F, Chermann JC, Rey F et al (1983) Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220:868–871
Popovic M, Sarngadharan MG, Read E, Gallo RC (1984) Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science 224:497–500
UNAIDS JUNPOHA (2012) UNAIDS report on the global AIDS epidemic 2012. In: unaids.org. http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2012/gr2012/20121120_UNAIDS_Global_Report_2012_en.pdf. Accessed 21 Mar 2013
Engelman A, Cherepanov P (2012) The structural biology of HIV-1: mechanistic and therapeutic insights. Nat Rev Microbiol 10:279–290
De Clercq E (2009) The history of antiretrovirals: key discoveries over the past 25 years. Rev Med Virol 19:287–299
Jaskolski M, Alexandratos JN, Bujacz G, Wlodawer A (2009) Piecing together the structure of retroviral integrase, an important target in AIDS therapy. FEBS J 276:2926–2946
Cherepanov P, Maertens GN, Hare S (2011) Structural insights into the retroviral DNA integration apparatus. Curr Opin Struct Biol 21:249–256
Li X, Krishnan L, Cherepanov P, Engelman A (2011) Structural biology of retroviral DNA integration. Virology 411:194–205
Cai M, Zheng R, Caffrey M et al (1997) Solution structure of the N-terminal zinc binding domain of HIV-1 integrase. Nat Struct Biol 4:567–577
Eijkelenboom AP, van den Ent FM, Vos A et al (1997) The solution structure of the amino-terminal HHCC domain of HIV-2 integrase: a three-helix bundle stabilized by zinc. Curr Biol 7:739–746
Nowotny M (2009) Retroviral integrase superfamily: the structural perspective. EMBO Rep 10:144–151
Dyda F, Hickman AB, Jenkins TM et al (1994) Crystal structure of the catalytic domain of HIV-1 integrase: similarity to other polynucleotidyl transferases. Science 266:1981–1986
Eijkelenboom AP, Lutzke RA, Boelens R et al (1995) The DNA-binding domain of HIV-1 integrase has an SH3-like fold. Nat Struct Biol 2:807–810
Hare S, Gupta SS, Valkov E et al (2010) Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464:232–236
Maertens GN, Hare S, Cherepanov P (2010) The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature 468:326–329
Hare S, Maertens GN, Cherepanov P (2012) 3'-Processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J 31:3020–3028
Wu X, Li Y, Crise B et al (2005) Weak palindromic consensus sequences are a common feature found at the integration target sites of many retroviruses. J Virol 79:5211–5214
Holman AG, Coffin JM (2005) Symmetrical base preferences surrounding HIV-1, avian sarcoma/leukosis virus, and murine leukemia virus integration sites. Proc Natl Acad Sci U S A 102:6103–6107
Lewinski MK, Yamashita M, Emerman M et al (2006) Retroviral DNA integration: viral and cellular determinants of target-site selection. PLoS Pathog 2:e60
Ciuffi A, Llano M, Poeschla E et al (2005) A role for LEDGF/p75 in targeting HIV DNA integration. Nat Med 11:1287–1289
Ge H, Si Y, Roeder RG (1998) Isolation of cDNAs encoding novel transcription coactivators p52 and p75 reveals an alternate regulatory mechanism of transcriptional activation. EMBO J 17:6723–6729
Eidahl JO, Crowe BL, North JA et al (2013) Structural basis for high-affinity binding of LEDGF PWWP to mononucleosomes. Nucleic Acids Res 41:3924–3936
Wu H, Zeng H, Lam R et al (2011) Structural and Histone Binding Ability Characterizations of Human PWWP Domains. PLoS One 6:e18919
Llano M, Vanegas M, Hutchins N et al (2006) Identification and characterization of the chromatin-binding domains of the HIV-1 integrase interactor LEDGF/p75. J Mol Biol 360:760–773
Maertens G, Cherepanov P, Debyser Z et al (2004) Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75. J Biol Chem 279:33421–33429
Tsutsui KM, Sano K, Hosoya O et al (2011) Nuclear protein LEDGF/p75 recognizes supercoiled DNA by a novel DNA-binding domain. Nucleic Acids Res 39:5067–5081
De Rijck J, Bartholomeeusen K, Ceulemans H et al (2010) High-resolution profiling of the LEDGF/p75 chromatin interaction in the ENCODE region. Nucleic Acids Res 38:6135–6147
Cherepanov P, Sun Z-YJ, Rahman S et al (2005) Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75. Nat Struct Mol Biol 12:526–532
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
Schrijvers R, De Rijck J, Demeulemeester J 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
Wang H, Jurado KA, Wu X et al (2012) 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 40:11518
Cherepanov P, Maertens G, Proost 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
Emiliani S, Mousnier A, Busschots K 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
Busschots K, Voet A, De Maeyer M et al (2007) Identification of the LEDGF/p75 binding site in HIV-1 integrase. J Mol Biol 365:1480–1492
Hombrouck A, De Rijck J, Hendrix J et al (2007) Virus evolution reveals an exclusive role for LEDGF/p75 in chromosomal tethering of HIV. PLoS Pathog 3:e47
Shun M-C, Raghavendra NK, Vandegraaff N et al (2007) LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev 21:1767–1778
Vandekerckhove L, Christ F, Van Maele B 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
Raghavendra NK, 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
Llano M, Delgado S, Vanegas M, Poeschla EM (2004) Lens epithelium-derived growth factor/p75 prevents proteasomal degradation of HIV-1 integrase. J Biol Chem 279:55570–55577
Maertens G, Cherepanov P, Pluymers W et al (2003) LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. J Biol Chem 278:33528–33539
Thys W, Bartholomeeusen K, Debyser Z (2011) Cellular cofactors of HIV integration. In: Neamati N (ed) HIV-1 integrase: mechanism and inhibitor design. Wiley, Hoboken, pp 105–130
Taltynov O, Desimmie BA, Demeulemeester J et al (2012) Cellular cofactors of Lentiviral integrase: from target validation to drug discovery. Mol Biol Int 2012:863405
Hazuda DJ, Hastings JC, Wolfe AL, Emini EA (1994) A novel assay for the DNA strand-transfer reaction of HIV-1 integrase. Nucleic Acids Res 22:1121–1122
Hazuda DJ, Felock P, Witmer M et al (2000) Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287:646–650
Espeseth AS, Felock P, Wolfe A 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
Fujishita T, Yoshinaga T, Sato A (2000) Aromatic heterocycle compounds having HIV integrase inhibiting activities. World patent WO 2000/039,086
Uenaka M, Kawata K, Nagai M, Endoh T (2000) Novel processes for the preparation of substituted propenone derivatives. World patent WO 2000/075,122
Marchand C, Zhang X, Pais GCG et al (2002) Structural determinants for HIV-1 integrase inhibition by beta-diketo acids. J Biol Chem 277:12596–12603
Goldgur Y, Craigie R, Cohen GH et al (1999) 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 96:13040–13043
Yoshinaga T, Sato A, Fujishita T, Fujiwara T (2002) S-1360: in vitro activity of a new HIV-1 integrase inhibitor in clinical development. In: 9th Conference on retroviruses and opportunistic infections. Seattle, February 22–28 2002.
Grobler JA, Stillmock K, Hu B et al (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
Rosemond MJC, St John-Williams L, Yamaguchi T et al (2004) Enzymology of a carbonyl reduction clearance pathway for the HIV integrase inhibitor, S-1360: role of human liver cytosolic aldo-keto reductases. Chem Biol Interact 147:129–139
Zhuang L, Wai JS, Embrey MW et al (2003) Design and synthesis of 8-hydroxy-[1, 6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells. J Med Chem 46:453–456
Summa V, Petrocchi A, Pace P et al (2004) Discovery of alpha, gamma-diketo acids as potent selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase. J Med Chem 47:14–17
Summa V, Petrocchi A, Matassa VG et al (2004) HCV NS5b RNA-dependent RNA polymerase inhibitors: from alpha, gamma-diketoacids to 4,5-dihydroxypyrimidine- or 3-methyl-5-hydroxypyrimidinonecarboxylic acids. Design and synthesis. J Med Chem 47:5336–5339
Petrocchi A, Koch U, Matassa VG et al (2007) From dihydroxypyrimidine carboxylic acids to carboxamide HIV-1 integrase inhibitors: SAR around the amide moiety. Bioorg Med Chem Lett 17:350–353
Summa V, Petrocchi A, Matassa VG et al (2006) 4,5-Dihydroxypyrimidine carboxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic profiles in preclinical species. J Med Chem 49:6646–6649
Anthony NJ, Gomez RP, Young SD et al (2002) Aza- and polyaza-naphthalenyl carboxamides useful as HIV integrase inhibitors. World patent WO 2002/030,931
Hazuda DJ, Young SD, Guare JP et al (2004) Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques. Science 305:528–532
Little S, Drusano G, Schooley R et al (2005) Antiretroviral effect of L-000870810, a novel HIV-1 integrase inhibitor, in HIV-1-infected patients. In: 12th Conference on retroviruses and opportunistic infections. Boston, 22–25 February 2005
Egbertson MS, Moritz HM, Melamed JY et al (2007) A potent and orally active HIV-1 integrase inhibitor. Bioorg Med Chem Lett 17:1392–1398
Pace P, Di Francesco ME, Gardelli C et al (2007) Dihydroxypyrimidine-4-carboxamides as novel potent and selective HIV integrase inhibitors. J Med Chem 50:2225–2239
Summa V, Petrocchi A, Bonelli F 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
Markowitz M, Morales-Ramirez JO, Nguyen B-Y et al (2006) 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 43:509–515
Steigbigel RT, Cooper DA, Teppler H et al (2010) Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clin Infect Dis 50:605–612
Lennox JL, DeJesus E, Lazzarin A et al (2009) Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 374:796–806
Eron JJ, Young B, Cooper DA et al (2010) Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet 375:396–407
Sato M, Motomura T, Aramaki H et al (2006) Novel HIV-1 integrase inhibitors derived from quinolone antibiotics. J Med Chem 49:1506–1508
Sato M, Kawakami H, Motomura T et al (2009) Quinolone carboxylic acids as a novel monoketo acid class of human immunodeficiency virus type 1 integrase inhibitors. J Med Chem 52:4869–4882
Shimura K, Kodama E, Sakagami Y 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
Lepist E-I, Phan TK, Roy A et al (2012) Cobicistat boosts the intestinal absorption of transport substrates, including HIV protease inhibitors and GS-7340, in vitro. Antimicrob Agents Chemother 56:5409–5413
Sax PE, DeJesus E, Mills A et al (2012) Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet 379:2439–2448
DeJesus E, Rockstroh JK, Henry K et al (2012) Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet 379:2429–2438
Molina J-M, Lamarca A, Andrade-Villanueva J 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
Valkov E, Gupta SS, Hare S et al (2009) Functional and structural characterization of the integrase from the prototype foamy virus. Nucleic Acids Res 37:243–255
Hare S, Vos AM, Clayton RF et al (2010) Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc Natl Acad Sci U S A 107:20057–20062
Dicker IB, Samanta HK, Li Z et al (2007) Changes to the HIV long terminal repeat and to HIV integrase differentially impact HIV integrase assembly, activity, and the binding of strand transfer inhibitors. J Biol Chem 282:31186–31196
Langley DR, Samanta HK, Lin Z et al (2008) The terminal (catalytic) adenosine of the HIV LTR controls the kinetics of binding and dissociation of HIV integrase strand transfer inhibitors. Biochemistry 47:13481–13488
Grobler JA, McKenna PM, Ly S et al (2009) Functionally irreversible inhibition of integration by slowly dissociating strand transfer inhibitors. In: 10th International workshop on clinical pharmacology of HIV therapy, Amsterdam, 15–17 April 2009
Hightower KE, Wang R, Deanda F et al (2011) Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than Raltegravir and Elvitegravir from wild type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes. Antimicrob Agents Chemother 55:4552–4559
Dicker I, Terry B, Protack T et al Longer integrase inhibitor dissociation half-lives induce persistent anti-HIV effects in cell culture. In: 18th Conference on retroviruses and opportunistic infections, Boston, 27 February–2 March 2011
Hare S, Smith SJ, Métifiot M et al (2011) Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol 80:565–572
Gatell JM, Katlama C, Grinsztejn B et al (2010) Long-term efficacy and safety of the HIV integrase inhibitor raltegravir in patients with limited treatment options in a Phase II study. J Acquir Immune Defic Syndr 53:456–463
Fransen S, Gupta S, Danovich R et al (2009) Loss of raltegravir susceptibility by human immunodeficiency virus type 1 is conferred via multiple nonoverlapping genetic pathways. J Virol 83:11440–11446
Hatano H, Lampiris H, Fransen S et al (2010) Evolution of integrase resistance during failure of integrase inhibitor-based antiretroviral therapy. J Acquir Immune Defic Syndr 54:389–393
Wittkop L, Breilh D, Da Silva D et al (2009) Virological and immunological response in HIV-1-infected patients with multiple treatment failures receiving raltegravir and optimized background therapy, ANRS CO3 Aquitaine Cohort. J Antimicrob Chemother 63:1251–1255
Armenia D, Vandenbroucke I, Fabeni L et al (2012) Study of genotypic and phenotypic HIV-1 dynamics of integrase mutations during raltegravir treatment: a refined analysis by ultra-deep 454 pyrosequencing. J Infect Dis 205:557–567
Cooper DA, Steigbigel RT, Gatell JM et al (2008) Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 359:355–365
Malet I, Delelis O, Valantin M-A et al (2008) Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob Agents Chemother 52:1351–1358
Blanco J-L, Varghese V, Rhee S-Y et al (2011) HIV-1 integrase inhibitor resistance and its clinical implications. J Infect Dis 203:1204–1214
Métifiot M, Vandegraaff N, Maddali K et al (2011) Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143. AIDS 25:1175–1178
Reuman EC, Bachmann MH, Varghese V et al (2010) Panel of prototypical raltegravir-resistant infectious molecular clones in a novel integrase-deleted cloning vector. Antimicrob Agents Chemother 54:934–936
Abram ME, Hluhanich RM, Goodman DD et al (2013) Impact of primary Elvitegravir resistance-associated mutations in HIV-1 integrase on drug susceptibility and viral replication fitness. Antimicrob Agents Chemother 57:2654–2663
Goethals O, Van Ginderen M, Vos A et al (2011) Resistance to raltegravir highlights integrase mutations at codon 148 in conferring cross-resistance to a second-generation HIV-1 integrase inhibitor. Antiviral Res 91:167–176
Goethals O, Clayton R, Van Ginderen M et al (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
Malet I, Delelis O, Soulie C et al (2009) Quasispecies variant dynamics during emergence of resistance to raltegravir in HIV-1-infected patients. J Antimicrob Chemother 63:795–804
Winters MA, Lloyd RM, Shafer RW et al (2012) Development of elvitegravir resistance and linkage of integrase inhibitor mutations with protease and reverse transcriptase resistance mutations. PLoS One 7:e40514
Kobayashi M, Yoshinaga T, Seki T et al (2011) In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother 55:813–821
Canducci F, Ceresola ER, Boeri E et al (2011) Cross-resistance profile of the novel integrase inhibitor Dolutegravir (S/GSK1349572) using clonal viral variants selected in patients failing raltegravir. J Infect Dis 204:1811–1815
Nichols G, Mills A, Grossberg R et al (2012) 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 15:18112
Johnson VA, Calvez V, Günthard HF et al (2013) Update of the drug resistance mutations in HIV-1: March 2013. Top Antivir Med 21:6–14
Krishnan L, Li X, Naraharisetty HL et al (2010) Structure-based modeling of the functional HIV-1 intasome and its inhibition. Proc Natl Acad Sci U S A 107:15910–15915
Nachega JB, Parienti J-J, Uthman O et al (2012) Regimen simplification in HIV infection toward once-daily dosing and fixed-dose combinations: a meta-analysis and sequential analysis of randomized controlled trials. In: XIX international AIDS conference, Washington, 22–27 July 2012
Thompson MA, Aberg JA, Cahn P et al (2010) Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA 304:321–333
Marinello J, Marchand C, Mott BT 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
Kawasuji T, Johns BA, Yoshida H et al (2012) Carbamoyl pyridone HIV-1 integrase inhibitors. 1. Molecular design and establishment of an advanced two-metal binding pharmacophore. J Med Chem 55:8735–8744
Kawasuji T, Johns BA, Yoshida H et al (2013) Carbamoyl pyridone HIV-1 integrase inhibitors. 2. Bi- and tricyclic derivatives result in superior antiviral and pharmacokinetic profiles. J Med Chem 56:1124–1135
Johns BA, Kawasuji T, Weatherhead JG et al (2013) Carbamoyl Pyridone HIV-1 integrase inhibitors 3. A diastereomeric approach to chiral non-racemic tricyclic ring systems and the discovery of S/GSK1349572 (Dolutegravir) and S/GSK1265744. J Med Chem 56:5901–5916
Yoshinaga T, Kobayashi M, Seki T et al (2012) Antiviral characteristics of S/GSK1265744, an HIV Integrase Inhibitor (INI) dosed by oral or long-acting parenteral injection. In: 52nd interscience conference on antimicrobial agents and chemotherapy, San Francisco, 9–12 September 2012
Andrews C, Gettie A, Russell-Lodrigue K et al Long-acting parenteral formulation of GSK1265744 protects macaques against repeated intrarectal challenges with SHIV. In: 20th Conference on retroviruses and opportunistic infections, Atlanta, 3–6 March 2013
Spreen W, Ford SL, Chen S et al (2012) Pharmacokinetics, safety and tolerability of the HIV integrase inhibitor S/GSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults. In: XIX international AIDS conference, Washington, 22–27 July 2012
van Lunzen J, Maggiolo F, Arribas JR et al (2012) Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis 12:111–118
Raffi F, Rachlis A, Stellbrink H-J et al (2013) Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet 381:735–743
Stellbrink H-J, Reynes J, Lazzarin A et al (2012) Dolutegravir in combination therapy exhibits rapid and sustained antiviral response in ARV-naïve adults: 96-week results from SPRING-1. In: 19th conference on retroviruses and opportunistic infections. Seattle, 5–8 March 2012
Eron JJ, Clotet B, Durant J et al (2013) Safety and efficacy of Dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING study. J Infect Dis 207:740–748
Garvey EP, Johns BA, Gartland MJ et al (2008) The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral. Antimicrob Agents Chemother 52:901–908
Johns BA, Kawasuji T, Weatherhead JG et al (2013) Naphthyridinone (NTD) integrase inhibitors: N1 protio and methyl combination substituent effects with C3 amide groups. Bioorg Med Chem Lett 23:422–425
Boros EE, Edwards CE, Foster SA et al (2009) Synthesis and antiviral activity of 7-benzyl-4-hydroxy-1,5-naphthyridin-2(1H)-one HIV integrase inhibitors. J Med Chem 52:2754–2761
Reddy YS, Min SS, Borland J et al (2007) Safety and pharmacokinetics of GSK364735, a human immunodeficiency virus type 1 integrase inhibitor, following single and repeated administration in healthy adult subjects. Antimicrob Agents Chemother 51:4284–4289
Plewe MB, Butler SL, Dress KR et al (2009) Azaindole hydroxamic acids are potent HIV-1 integrase inhibitors. J Med Chem 52:7211–7219
Bauer L, Exner O (1974) The chemistry of hydroxamic acids and N-Hydroxyimides. Angew Chem Int Ed Engl 13:376–384
Tanis SP, Plewe MB, Johnson TW et al (2010) Azaindole N-methyl hydroxamic acids as HIV-1 integrase inhibitors-II. The impact of physicochemical properties on ADME and PK. Bioorg Med Chem Lett 20:7429–7434
Pryde DC, Webster R, Butler SL et al (2013) Discovery of an HIV integrase inhibitor with an excellent resistance profile. Med Chem Commun 4:709
Johnson TW, Tanis SP, Butler SL et al (2011) Design and synthesis of novel N-hydroxy-dihydronaphthyridinones as potent and orally bioavailable HIV-1 integrase inhibitors. J Med Chem 54:3393–3417
Jin H, Cai RZ, Schacherer L et al (2006) Design, synthesis, and SAR studies of novel and highly active tri-cyclic HIV integrase inhibitors. Bioorg Med Chem Lett 16:3989–3992
Metobo SE, Jin H, Tsiang M, Kim CU (2006) Design, synthesis, and biological evaluation of novel tricyclic HIV-1 integrase inhibitors by modification of its pyridine ring. Bioorg Med Chem Lett 16:3985–3988
Fardis M, Jin H, Jabri S et al (2006) Effect of substitution on novel tricyclic HIV-1 integrase inhibitors. Bioorg Med Chem Lett 16:4031–4035
Jin H, Wright M, Pastor R et al (2008) Tricyclic HIV integrase inhibitors: potent and orally bioavailable C5-aza analogs. Bioorg Med Chem Lett 18:1388–1391
Jin H, Metobo S, Jabri S et al (2009) Tricyclic HIV integrase inhibitors V. SAR studies on the benzyl moiety. Bioorg Med Chem Lett 19:2263–2265
Jones GS, Yu F, Zeynalzadegan A et al (2009) Preclinical evaluation of GS-9160, a novel inhibitor of human immunodeficiency virus type 1 integrase. Antimicrob Agents Chemother 53:1194–1203
Metobo S, Mish M, Jin H et al (2009) Tricyclic HIV integrase inhibitors: VI. SAR studies of “benzyl flipped” C3-substituted pyrroloquinolines. Bioorg Med Chem Lett 19:1187–1190
Wai JS, Kim B, Fisher TE et al (2007) Dihydroxypyridopyrazine-1,6-dione HIV-1 integrase inhibitors. Bioorg Med Chem Lett 17:5595–5599
Crescenzi B, Gardelli C, Muraglia E et al (2003) N-Substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase. World patent WO 2003/035,077
Egbertson MS, Wai JS, Cameron M, Hoerrner RS (2011) Discovery of MK-0536: a potential second-generation HIV-1 integrase strand transfer inhibitor with a high genetic barrier to mutation. In: (Kazmierski WM ed) Antiviral drugs from basic discovery through clinical trials. Wiley, Hoboken, pp 163–180
Métifiot M, Johnson B, Smith S et al (2011) MK-0536 inhibits HIV-1 integrases resistant to raltegravir. Antimicrob Agents Chemother 55:5127–5133
Fisher TE, Kim B, Staas DD et al (2007) 8-Hydroxy-3,4-dihydropyrrolo[1,2-a]pyrazine-1(2H)-one HIV-1 integrase inhibitors. Bioorg Med Chem Lett 17:6511–6515
Langford HM, Williams PD, Homnick CF et al (2008) Design and synthesis of substituted 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamides, novel HIV-1 integrase inhibitors. Bioorg Med Chem Lett 18:721–725
Wiscount CM, Williams PD, Tran LO et al (2008) 10-Hydroxy-7,8-dihydropyrazino[1“,2”:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-diones: potent, orally bioavailable HIV-1 integrase strand-transfer inhibitors with activity against integrase mutants. Bioorg Med Chem Lett 18:4581–4583
Vacca J, Wai J, Fisher T et al (2007) Discovery of MK-2048: subtle changes confer unique resistance properties to a series of tricyclic hydroxypyrrole integrase strand transfer inhibitors. In: 4th IAS conference on HIV pathogenesis, treatment and prevention. Sydney, 22–25 July 2007
Van Wesenbeeck L, Rondelez E, Feyaerts M et al (2011) Cross-resistance profile determination of two second-generation HIV-1 integrase inhibitors using a panel of recombinant viruses derived from raltegravir-treated clinical isolates. Antimicrob Agents Chemother 55:321–325
Bar-Magen T, Sloan RD, Donahue DA et al (2010) Identification of novel mutations responsible for resistance to MK-2048, a second-generation HIV-1 integrase inhibitor. J Virol 84:9210–9216
Cotelle P (2011) 3-Hydroxy-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-ones as new HIV-1 integrase inhibitors WO2011/046,873 A1. Expert Opin Ther Pat 21:1799–1804
Naidu BN, Peese K, Dicker IB et al (2011) HIV integrase inhibitors. World patent WO 2011/046,873
Gardelli C, Nizi E, Muraglia E et al (2007) Discovery and synthesis of HIV integrase inhibitors: development of potent and orally bioavailable N-methyl pyrimidones. J Med Chem 50:4953–4975
Muraglia E, Kinzel O, Gardelli C et al (2008) Design and synthesis of bicyclic pyrimidinones as potent and orally bioavailable HIV-1 integrase inhibitors. J Med Chem 51:861–874
Donghi M, Kinzel OD, Summa V (2009) 3-Hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylates–a new class of HIV-1 integrase inhibitors. Bioorg Med Chem Lett 19:1930–1934
Jones ED, Vandegraaff N, Le G et al (2010) Design of a series of bicyclic HIV-1 integrase inhibitors. Part 1: selection of the scaffold. Bioorg Med Chem Lett 20:5913–5917
Jones ED, Coates JAV, Rhodes DI et al (2008) Bicyclic pyrimidinones and uses thereof. World patent WO 2008/077,188
Le G, Vandegraaff N, Rhodes DI et al (2010) Design of a series of bicyclic HIV-1 integrase inhibitors. Part 2: azoles: effective metal chelators. Bioorg Med Chem Lett 20:5909–5912
Le G, Vandegraaff N, Rhodes DI et al (2010) Discovery of potent HIV integrase inhibitors active against raltegravir resistant viruses. Bioorg Med Chem Lett 20:5013–5018
Billamboz M, Bailly F, Barreca ML et al (2008) Design, synthesis, and biological evaluation of a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones as dual inhibitors of human immunodeficiency virus type 1 integrase and the reverse transcriptase RNase H domain. J Med Chem 51:7717–7730
Bailly F, Billamboz M, Christ F et al (2012) 2-hydroxyisoquinoline-1,3(2h,4h)-diones and related compounds useful as HIV replication inhibitors. World patent WO 2012/085,003
Billamboz M, Suchaud V, Bailly F et al (2013) 4-substituted 2-hydroxyisoquinoline-1,3(2H,4H)-diones as a novel class of HIV-1 integrase inhibitors. ACS Med Chem Lett 4:606–611
Desimmie BA, Demeulemeester J, Suchaud V et al (2013) 2-Hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs), novel inhibitors of HIV integrase with a high barrier to resistance. ACS Chem Biol 8:1187–1194
Zhao XZ, Semenova EA, Vu BC et al (2008) 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one-based HIV-1 integrase inhibitors. J Med Chem 51:251–259
Zhao XZ, Maddali K, Marchand C et al (2009) Diketoacid-genre HIV-1 integrase inhibitors containing enantiomeric arylamide functionality. Bioorg Med Chem 17:5318–5324
Métifiot M, Maddali K, Johnson BC et al (2013) Activities, crystal structures, and molecular dynamics of dihydro-1H-isoindole derivatives, inhibitors of HIV-1 integrase. ACS Chem Biol 8:209–217
Agrawal A, Desoto J, Fullagar JL et al (2012) Probing chelation motifs in HIV integrase inhibitors. Proc Natl Acad Sci U S A 109:2251–2256
Al-Mawsawi LQ, Neamati N (2011) Allosteric inhibitor development targeting HIV-1 integrase. ChemMedChem 6:228–241
Demeulemeester J, Christ F, De Maeyer M, Debyser Z (2012) Fueling HIV-1 integrase drug design with structural insights. Drug Discov Today Technol 9:e205–e212
Engelman A, Kessl JJ, Kvaratskhelia M (2013) Allosteric inhibition of HIV-1 integrase activity. Curr Opin Chem Biol 17:339–345
Wielens J, Headey SJ, Deadman JJ et al (2011) Fragment-based design of ligands targeting a novel site on the integrase enzyme of human immunodeficiency virus 1. ChemMedChem 6:258–261
Wielens J, Headey SJ, Rhodes DI et al (2013) Parallel screening of low molecular weight fragment libraries: do differences in methodology affect hit identification? J Biomol Screen 18:147–159
Rhodes DI, Peat TS, Vandegraaff N et al (2011) Structural basis for a new mechanism of inhibition of HIV-1 integrase identified by fragment screening and structure-based design. Antivir Chem Chemother 21:155–168
Peat TS, Rhodes DI, Vandegraaff N et al (2012) Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design. PLoS One 7:e40147
Wielens J, Headey SJ, Jeevarajah D et al (2010) Crystal structure of the HIV-1 integrase core domain in complex with sucrose reveals details of an allosteric inhibitory binding site. FEBS Lett 584:1455–1462
Kessl JJ, Eidahl JO, Shkriabai N et al (2009) An allosteric mechanism for inhibiting HIV-1 integrase with a small molecule. Mol Pharmacol 76:824–832
Shkriabai N, Patil SS, Hess S et al (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
Du L, Zhao Y-X, Yang L-M et al (2008) Symmetrical 1-pyrrolidineacetamide showing anti-HIV activity through a new binding site on HIV-1 integrase. Acta Pharmacol Sin 29:1261–1267
Christ F, Voet A, Marchand A et al (2010) Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat Chem Biol 6:442–448
Cherepanov P, Ambrosio ALB, Rahman S et al (2005) Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc Natl Acad Sci U S A 102:17308–17313
Llano M, Saenz DT, Meehan A et al (2006) An essential role for LEDGF/p75 in HIV integration. Science 314:461–464
De Rijck J, Vandekerckhove L, Gijsbers R 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
Hayouka Z, Rosenbluh J, Levin A et al (2007) Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium. Proc Natl Acad Sci U S A 104:8316–8321
Hou Y, McGuinness DE, Prongay AJ et al (2008) Screening for antiviral inhibitors of the HIV integrase-LEDGF/p75 interaction using the AlphaScreen luminescent proximity assay. J Biomol Screen 13:406–414
Du L, Zhao Y, Chen J et al (2008) 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 375:139–144
De Luca L, Barreca ML, Ferro S et al (2009) Pharmacophore-based discovery of small-molecule inhibitors of protein-protein interactions between HIV-1 integrase and cellular cofactor LEDGF/p75. ChemMedChem 4:1311–1316
Fan X, Zhang F-H, Al-Safi RI et al (2011) 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 19:4935–4952
De Luca L, Ferro S, Gitto R et al (2010) Small molecules targeting the interaction between HIV-1 integrase and LEDGF/p75 cofactor. Bioorg Med Chem 18:7515–7521
Molteni V, Greenwald J, Rhodes D et al (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
Maignan S, Guilloteau JP, Zhou-Liu Q et al (1998) Crystal structures of the catalytic domain of HIV-1 integrase free and complexed with its metal cofactor: high level of similarity of the active site with other viral integrases. J Mol Biol 282:359–368
Christ F, Shaw S, Demeulemeester J et al (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
Bardiot D, Chaltin P, Christ F et al (2010) Thieno [2, 3-B] pyridine derivatives as viral replication inhibitors. World patent WO 2010/130,842
Bell AS, Gardner IB, Pryde DC et al (2012) Inhibitors of HIV replication. World patent WO 2012/066,442
Chaltin P, Christ F, Debyser Z et al (2012) Novel antiviral compounds. World patent WO 2012/065,963
Chaltin P, Debyser Z, De Maeyer M et al (2011) Novel viral replication inhibitors. World patent 2011/015,641
Carlens G, Chaltin P, Christ F et al (2011) Novel antiviral compounds. World patent WO 2011/076,765
Fenwick C, Bethell R, Bonneau P et al (2011) Identification of BI-C, a novel HIV-1 non-catalytic site integrase inhibitor. 18th Conference on retroviruses and opportunistic infections, Boston, 27 February–2 March 2011
Kessl JJ, Jena N, Koh Y et al (2012) Multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem 287:16801–16811
Tsantrizos YS, Boes M, Brochu C et al (2007) Inhibitors of human immunodeficiency virus replication. World patent WO 2007/131350
Tsantrizos YS, Bailey MD, Bilodeau F et al (2009) Inhibitors of human immunodeficiency virus replication. World patent WO 2009/062,285
Carson R, Fader L, Kawai S et al (2009) Inhibitors of human immunodeficiency virus replication. World patent WO 2009/062,288
Yoakim C, Bailey MD, Bilodeau F et al (2010) Inhibitors of human immunodeficiency virus Replication. World patent WO 2010/130,034
Fukuhara N, Fernandez E, Ebert J et al (2004) Conformational variability of nucleo-cytoplasmic transport factors. J Biol Chem 279:2176–2181
Fenwick C, Bethell R, Cordingley M (2011) 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. In: 51st Interscience conference on antimicrobial agents and chemotherapy, Chicago, 17–20 September 2011
Brown A, McSharry J, Kulawy R (2011) Pharmacodynamics of BI 224436 for HIV-1 in an in vitro hollow fiber infection model system. 51st Interscience conference on antimicrobial agents and chemotherapy, Chicago, 17–20 September 2011
Yoakim C, Amad M, Bailey M (2011) Preclinical profile of BI 224436, a novel HIV-1 non-catalytic site integrase inhibitor. In: 51st Interscience conference on antimicrobial agents and chemotherapy, Chicago, 17–20 September 2011
Aslanyan S, Ballow C, Sabo J (2011) Safety and pharmacokinetics (PK) of single rising oral doses of a novel HIV integrase inhibitor in healthy volunteers. In: 51st Interscience conference on antimicrobial agents and chemotherapy, Chicago, 17–20 September 2011
Tsiang M, Jones GS, Niedziela-Majka A et al (2012) New class of HIV-1 integrase (IN) inhibitors with a dual mode of action. J Biol Chem 287:21189–21203
Babaoglu K, Bjornson K, Guo H et al (2012) 2-Quinolinyl- acetic acid derivatives as HIV antiviral compounds. World patent WO 2012/003,498
Babaoglu K, Bjornson K, Guo H et al (2012) Napht- 2 -Ylacetic acid derivatives to treat Aids. World patent WO 2012/003497
Mitchell ML, Roethle PA, Xu L et al (2012) Benzothiazole compounds and their pharmaceutical use. World patent WO 2012/145,728
Li W, De Croos P, Fandrick KR et al (2012) Process for the preparation of an HIV integrase inhibitor. World patent WO 2012/138670
Li ZJ, Li Z, Luo L et al (2012) Solid state forms of HIV inhibitor. World patent WO 2012/138,669
Jurado KA, Wang H, Slaughter A et al (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
Feng L, Sharma A, Slaughter A et al (2013) The A128T resistance mutation reveals aberrant protein multimerization as the primary mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem 288:15813–15820
Kessl JJ, Li M, Ignatov M 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
McKee CJ, Kessl JJ, Shkriabai N et al (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
Schrijvers R, Demeulemeester J, De Rijck J et al (2012) Characterization of rare LEDGF/p75 genetic variants identified in HIV-1 long-term non-progressors. AIDS 27:539–543
Demeulemeester J, Tintori C, Botta M et al (2012) Development of an alphascreen-based HIV-1 integrase dimerization assay for discovery of novel allosteric inhibitors. J Biomol Screen 17:618–628
Tsiang M, Jones GS, Hung M et al (2011) Dithiothreitol causes HIV-1 integrase dimer dissociation while agents interacting with the integrase dimer interface promote dimer formation. Biochemistry 50:1567–1581
Engelman A, Englund G, Orenstein JM et al (1995) Multiple effects of mutations in human immunodeficiency virus type 1 integrase on viral replication. J Virol 69:2729–2736
Desimmie BA, Schrijvers R, Demeulemeester J et al (2013) LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions. Retrovirology 10:57
Desimmie B, Schrijvers R, Vets S et al (2013) Incorporation of LEDGF/p75 in viral particles is crucial for HIV infectivity. In: 20th Conference on retroviruses and opportunistic infections, Atlanta, 3–6 March 2013
Desimmie BA, Humbert M, Lescrinier E et al (2012) Phage display-directed discovery of LEDGF/p75 binding cyclic peptide inhibitors of HIV replication. Mol Ther 20:2064–2075
Shen L, Rabi SA, Sedaghat AR et al (2011) A critical subset model provides a conceptual basis for the high antiviral activity of major HIV drugs. Sci Transl Med 3:91ra63
Fenwick CW, Tremblay S, Wardrop E et al Resistance studies with HIV-1 non-catalytic site integrase inhibitors. In: International workshop on HIV & hepatitis virus drug resistance and curative strategies. Cabo, 7–11 June 2011
Pendri A, Li G, Gerritz S et al (2012) Inhibitors of human immunodeficiency virus replication. World patent WO 2012/033,735
Naidu BN, Patel M (2013) Inhibitors of human immunodeficiency virus replication. World patent WO 2013/025584
Haydar SN, Johns BA, Velthuisen EJ (2013) Pyrrolopyridinone compounds and methods for treating HIV. World patent WO 2013/043,553
La Rosa De MA, Haydar SN, Johns BA, Velthuisen EJ (2012) Isoquinoline compounds and methods for treating HIV. World patent WO 2012/102,985
La Rosa De MA, Johns BA, Samano V et al (2013) Azaindole compounds and methods for treating HIV. World patent WO 2013/012,649
Hattori K, Kurihara N, Iwaki T et al (2013) HIV replication inhibitor. World patent WO 2013/002,357
Iwaki T, Tomita K (2013) HIV replication inhibitor. World patent WO 2013/062,028
Chasset S, Chevreuil F, Ledoussal B et al (2012) Inhibitors of viral replication, their process of preparation and their therapeutical uses. World patent WO 2012/140,243
Chasset S, Chevreuil F, Ledoussal B et al (2012) Inhibitors of viral replication, their process of preparation and their therapeutical uses. World patent WO 2012/137,181
Son JC, Kim BJ, Kim JH et al (2013) Novel antiviral pyrrolopyridine derivative and a production method for same. World patent WO 2013/073,875
Rhodes DI, Peat TS, Vandegraaff N et al (2011) Crystal structures of novel allosteric peptide inhibitors of HIV integrase identify new interactions at the LEDGF binding site. Chembiochem 12:2311–2315
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Demeulemeester, J., De Maeyer, M., Debyser, Z. (2013). HIV-1 Integrase Drug Discovery Comes of Age. In: Diederich, W., Steuber, H. (eds) Therapy of Viral Infections. Topics in Medicinal Chemistry, vol 15. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2013_33
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