hiv integrase inhibitors


Summary: Inhibitors of HIV INTEGRASE, an enzyme required for integration of viral DNA into cellular DNA.

Top Publications

  1. Fransen S, Karmochkine M, Huang W, Weiss L, Petropoulos C, Charpentier C. Longitudinal analysis of raltegravir susceptibility and integrase replication capacity of human immunodeficiency virus type 1 during virologic failure. Antimicrob Agents Chemother. 2009;53:4522-4 pubmed publisher
  2. Hu G, Li X, Zhang X, Li Y, Ma L, Yang L, 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;55:10108-17 pubmed publisher
    ..These findings could be helpful for anti-HIV drug discovery. ..
  3. Codoñer F, Pou C, Thielen A, Garcia F, Delgado R, Dalmau D, et al. Dynamic escape of pre-existing raltegravir-resistant HIV-1 from raltegravir selection pressure. Antiviral Res. 2010;88:281-6 pubmed publisher
  4. Mouscadet J, Arora R, André J, Lambry J, Delelis O, Malet I, et al. HIV-1 IN alternative molecular recognition of DNA induced by raltegravir resistance mutations. J Mol Recognit. 2009;22:480-94 pubmed publisher
    ..This study opens up new opportunities for the design of integrase inhibitors active against raltegravir-resistant viruses. ..
  5. Margot N, Hluhanich R, Jones G, Andreatta K, Tsiang M, McColl D, et al. In vitro resistance selections using elvitegravir, raltegravir, and two metabolites of elvitegravir M1 and M4. Antiviral Res. 2012;93:288-96 pubmed publisher
  6. Young B, Fransen S, Greenberg K, Thomas A, Martens S, St Clair M, et al. Transmission of integrase strand-transfer inhibitor multidrug-resistant HIV-1: case report and response to raltegravir-containing antiretroviral therapy. Antivir Ther. 2011;16:253-6 pubmed publisher
    ..This case illustrates an emerging need to consider the possibility of acquired INI resistance among newly diagnosed treatment-naive individuals harbouring multidrug-resistant HIV-1. ..
  7. Hurt C. Transmitted resistance to HIV integrase strand-transfer inhibitors: right on schedule. Antivir Ther. 2011;16:137-40 pubmed publisher
  8. Buzón M, Dalmau J, Puertas M, Puig J, Clotet B, Martinez Picado J. The HIV-1 integrase genotype strongly predicts raltegravir susceptibility but not viral fitness of primary virus isolates. AIDS. 2010;24:17-25 pubmed publisher
  9. Billamboz M, Bailly F, Lion C, Touati N, Vezin H, Calmels C, et al. Magnesium chelating 2-hydroxyisoquinoline-1,3(2H,4H)-diones, as inhibitors of HIV-1 integrase and/or the HIV-1 reverse transcriptase ribonuclease H domain: discovery of a novel selective inhibitor of the ribonuclease H function. J Med Chem. 2011;54:1812-24 pubmed publisher
    ..Experimental data suggest that the antiviral activity of 2-hydroxy-4-methoxycarbonylisoquinoline-1,3(2H,4H)-dione is probably due to the RNase H inhibition. ..

More Information


  1. Bar Magen T, Sloan R, Donahue D, Kuhl B, Zabeida A, Xu H, et al. Identification of novel mutations responsible for resistance to MK-2048, a second-generation HIV-1 integrase inhibitor. J Virol. 2010;84:9210-6 pubmed publisher
  2. Toropova A, Toropov A, Benfenati E, Gini G. Simplified molecular input-line entry system and International Chemical Identifier in the QSAR analysis of styrylquinoline derivatives as HIV-1 integrase inhibitors. Chem Biol Drug Des. 2011;77:343-60 pubmed publisher
    ..7715, R(m)(2) = 0.819, s = 0.329, F = 48 for the validation set. Thus, the InChI-based model is preferable. The described SMILES-based and InChI-based approaches have been checked with five random splits into the training and test sets. ..
  3. Kessl J, Eidahl J, Shkriabai N, Zhao Z, McKee C, Hess S, et al. An allosteric mechanism for inhibiting HIV-1 integrase with a small molecule. Mol Pharmacol. 2009;76:824-32 pubmed publisher
    ..The proposed mechanism of action and binding site for the small-molecule inhibitor identified in the present study provide an attractive venue for developing allosteric inhibitors of HIV-1 IN. ..
  4. De Luca L, Ferro S, Morreale F, Chimirri A. Inhibition of the interaction between HIV-1 integrase and its cofactor LEDGF/p75: a promising approach in anti-retroviral therapy. Mini Rev Med Chem. 2011;11:714-27 pubmed
    ..This article reviews the discovery and development of molecules capable of interrupting the LEDGF/p75-IN interaction reported to date. ..
  5. Garrido C, Soriano V, Geretti A, Zahonero N, Garcia S, Booth C, et al. Resistance associated mutations to dolutegravir (S/GSK1349572) in HIV-infected patients--impact of HIV subtypes and prior raltegravir experience. Antiviral Res. 2011;90:164-7 pubmed publisher
    ..T124A was more frequent in INI-naïve patients but E92Q and Q148H/R were only seen in raltegravir-experienced individuals. Thus, both HIV-1 subtype and raltegravir exposure may influence the antiviral activity of dolutegravir. ..
  6. Metifiot M, Marchand C, Pommier Y. HIV integrase inhibitors: 20-year landmark and challenges. Adv Pharmacol. 2013;67:75-105 pubmed publisher
    ..We also discuss the role of chromatin and host DNA repair factor for the completion of integration. ..
  7. Goethals O, Van Ginderen M, Vos A, Cummings M, Van Der Borght K, Van Wesenbeeck L, et al. Resistance to raltegravir highlights integrase mutations at codon 148 in conferring cross-resistance to a second-generation HIV-1 integrase inhibitor. Antiviral Res. 2011;91:167-76 pubmed publisher
    ..These findings will be important for the further discovery and profiling of next-generation INSTIs. ..
  8. Tsiang M, Jones G, Niedziela Majka A, Kan E, Lansdon E, Huang W, et al. New class of HIV-1 integrase (IN) inhibitors with a dual mode of action. J Biol Chem. 2012;287:21189-203 pubmed publisher
    ..For the first time, tBPQAs were demonstrated to be allosteric inhibitors of HIV-1 IN displaying a dual mode of action: inhibition of IN-viral DNA assembly and inhibition of IN-LEDGF interaction...
  9. Smith R, Raugi D, Kiviat N, Hawes S, Mullins J, Sow P, et al. Phenotypic susceptibility of HIV-2 to raltegravir: integrase mutations Q148R and N155H confer raltegravir resistance. AIDS. 2011;25:2235-41 pubmed publisher
    ..Further efforts are needed to improve access to HIV-2-active antiretrovirals, including raltegravir, in resource-limited areas where HIV-2 is endemic. ..
  10. Burger D. Drug-drug interactions with raltegravir. Eur J Med Res. 2009;14 Suppl 3:17-21 pubmed
    ..Raltegravir is not without drug-drug interactions but due to the lack of an effect on CYP450 or UGT by raltegravir and the broad therapeutic range of raltegravir itself, this agent can safely combined with almost all tested agents. ..
  11. Tang J, Maddali K, Pommier Y, Sham Y, Wang Z. Scaffold rearrangement of dihydroxypyrimidine inhibitors of HIV integrase: Docking model revisited. Bioorg Med Chem Lett. 2010;20:3275-9 pubmed publisher
    ..With this new model, docking results completely corroborated observed biological activities. This new model should provide a more accurate and improved platform for the design of new inhibitors of HIV IN. ..
  12. Ceccherini Silberstein F, Van Baelen K, Armenia D, Trignetti M, Rondelez E, Fabeni L, et al. Secondary integrase resistance mutations found in HIV-1 minority quasispecies in integrase therapy-naive patients have little or no effect on susceptibility to integrase inhibitors. Antimicrob Agents Chemother. 2010;54:3938-48 pubmed publisher
  13. Mesplede T, Quashie P, Wainberg M. Resistance to HIV integrase inhibitors. Curr Opin HIV AIDS. 2012;7:401-8 pubmed publisher
    b>HIV integrase inhibitors are potent antiretroviral drugs that efficiently decrease viral load in patients. Emergence of resistance mutations against this new class of drugs represents a threat to their long-term efficacy...
  14. Johnson M. Raltegravir use in special populations. Eur J Med Res. 2009;14 Suppl 3:43-6 pubmed
    ..Finally, although not licensed for use in pregnancy, raltegravir may need to be considered in some pregnant women with antiretroviral resistance or tolerability issues with current HAART regimens. ..
  15. Charpentier C, Larrouy L, Collin G, Damond F, Matheron S, Chene G, et al. In-vitro phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitor S/GSK1349572. AIDS. 2010;24:2753-5 pubmed publisher
    ..We found a seven-, 13- and 18-fold increase in EC?? values to S/GSK1349572 for the HIV-2 double (T97A + Y143C; G140S + Q148R) and triple (G140T + Q148R + N155H) mutants, respectively, obtained from two raltegravir-experienced patients. ..
  16. Marchand C, Maddali K, Metifiot M, Pommier Y. HIV-1 IN inhibitors: 2010 update and perspectives. Curr Top Med Chem. 2009;9:1016-37 pubmed
    ..Additionally, the targeting of IN cofactors such as LEDGF and Vpr will be discussed as novel strategies for the treatment of AIDS. ..
  17. Garrido C, Geretti A, Zahonero N, Booth C, Strang A, Soriano V, et al. Integrase variability and susceptibility to HIV integrase inhibitors: impact of subtypes, antiretroviral experience and duration of HIV infection. J Antimicrob Chemother. 2010;65:320-6 pubmed publisher known about the extent and predictors of polymorphisms potentially influencing the susceptibility to HIV integrase inhibitors (INIs). Genetic sequences of HIV integrase were obtained from INI-naive patients at two European clinics...
  18. Baldanti F, Paolucci S, Gulminetti R, Brandolini M, Barbarini G, Maserati R. Early emergence of raltegravir resistance mutations in patients receiving HAART salvage regimens. J Med Virol. 2010;82:116-22 pubmed publisher
    ..The effect of single and multiple mutations on integrase activity, raltegravir susceptibility, and on the capacity of viral replication remains to be elucidated. ..
  19. Li M, Zhou Y, Luo Q, Li Z. The 3D structures of G-quadruplexes of HIV-1 integrase inhibitors: molecular dynamics simulations in aqueous solution and in the gas phase. J Mol Model. 2010;16:645-57 pubmed publisher
    ..Our 3D structures for G1 and G2 will assist in understanding geometric formalism of G-quadruplex folding and may be helpful as a platform for rational anti-HIV drug design. ..
  20. Nagasawa J, Song J, Chen H, Kim H, Blazel J, Ouk S, et al. 6-Benzylamino 4-oxo-1,4-dihydro-1,8-naphthyridines and 4-oxo-1,4-dihydroquinolines as HIV integrase inhibitors. Bioorg Med Chem Lett. 2011;21:760-3 pubmed publisher
    ..SAR studies on the quinolone carboxylic acid class of HIV-1 integrase inhibitors focused on improving the metabolic stability and led to the discovery of 27 and 38. ..
  21. Quashie P, Mesplede T, Wainberg M. Evolution of HIV integrase resistance mutations. Curr Opin Infect Dis. 2013;26:43-9 pubmed publisher
    ..Because of the susceptibility to drug resistance, INSTIs should always be used together with other effective ARV drugs. ..
  22. Seegulam M, Ratner L. Integrase inhibitors effective against human T-cell leukemia virus type 1. Antimicrob Agents Chemother. 2011;55:2011-7 pubmed publisher
    ..These data support the administration of raltegravir and other integrase inhibitors as treatments for patients with HTLV-1-associated diseases. ..
  23. Hu Z, Kuritzkes D. Effect of raltegravir resistance mutations in HIV-1 integrase on viral fitness. J Acquir Immune Defic Syndr. 2010;55:148-55 pubmed publisher
    ..These findings correspond well with the clinical trials data and help explain the temporal pattern of RAL resistance evolution. ..
  24. Molina J, Lamarca A, Andrade Villanueva J, Clotet B, Clumeck N, Liu Y, et al. 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. 2012;12:27-35 pubmed publisher
    ..Since elvitegravir can be given once a day compared with twice a day for raltegravir, elvitegravir might improve patients' adherence. Gilead Sciences. ..
  25. Hayouka Z, Levin A, Maes M, Hadas E, Shalev D, Volsky D, et al. Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370. Biochem Biophys Res Commun. 2010;394:260-5 pubmed publisher
    ..We conclude that the full LEDGF 361-370 peptide is a potent HIV-1 inhibitor and may be used for further development as an anti-HIV lead compound...
  26. Di Santo R. Diketo acids derivatives as dual inhibitors of human immunodeficiency virus type 1 integrase and the reverse transcriptase RNase H domain. Curr Med Chem. 2011;18:3335-42 pubmed
    ..The results of the activities showed by pyrrolyl and quinolonyl diketo acids are reported and discussed. ..
  27. Mouscadet J, Tchertanov L. Raltegravir: molecular basis of its mechanism of action. Eur J Med Res. 2009;14 Suppl 3:5-16 pubmed
    ..In this review, we describe the mechanism of action of this drug and the main data relating to its use in vivo, together with recent structural data important to our understanding of the origin of viral resistance. ..
  28. Koelsch K, Cooper D. Integrase inhibitors in salvage therapy regimens for HIV-1 infection. Curr Opin HIV AIDS. 2009;4:518-23 pubmed publisher
    ..The major limitation for the use of integrase inhibitors is a potentially low threshold for viral drug resistance, so functional monotherapy must be avoided. ..
  29. Schrijvers R, De Rijck J, Demeulemeester J, Adachi N, Vets S, Ronen K, 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:e1002558 pubmed publisher
    ..These results further support the potential of LEDGINs as allosteric integrase inhibitors. ..
  30. Métifiot M, Maddali K, Johnson B, Hare S, Smith S, Zhao X, et al. Activities, crystal structures, and molecular dynamics of dihydro-1H-isoindole derivatives, inhibitors of HIV-1 integrase. ACS Chem Biol. 2013;8:209-17 pubmed publisher
    ..Molecular dynamics analyses of the HIV-1 intasome highlight the importance of the viral DNA in drug potency. ..
  31. van Wesenbeeck L, Rondelez E, Feyaerts M, Verheyen A, van der Borght K, Smits V, et al. 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. 2011;55:321-5 pubmed publisher
    ..The order according to decreasing susceptibility is compound G, MK-2048, and EVG. ..
  32. Min S, Song I, Borland J, Chen S, Lou Y, Fujiwara T, et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother. 2010;54:254-8 pubmed publisher
    ..S/GSK1349572 had no impact on midazolam exposure, indicating that it does not modulate CYP3A activity. The PK profile suggests that once-daily, low milligram doses will achieve therapeutic concentrations. ..
  33. Sangeetha B, Muthukumaran R, Amutha R. Pharmacophore modelling and electronic feature analysis of hydroxamic acid derivatives, the HIV integrase inhibitors. SAR QSAR Environ Res. 2013;24:753-71 pubmed publisher
  34. Hatano H, Lampiris H, Fransen S, Gupta S, Huang W, Hoh R, et al. Evolution of integrase resistance during failure of integrase inhibitor-based antiretroviral therapy. J Acquir Immune Defic Syndr. 2010;54:389-93 pubmed publisher
    ..This resistance evolution is gradual and associated with declines in replicative capacity. ..
  35. Quercia R, Dam E, Perez Bercoff D, Clavel F. Selective-advantage profile of human immunodeficiency virus type 1 integrase mutants explains in vivo evolution of raltegravir resistance genotypes. J Virol. 2009;83:10245-9 pubmed publisher
    ..This finding likely explains why N155H can be selected early in the course of RAL resistance evolution in vivo but is later replaced by genotypes that include Q148HKR. ..
  36. Wang Z, Tang J, Salomon C, Dreis C, Vince R. Pharmacophore and structure-activity relationships of integrase inhibition within a dual inhibitor scaffold of HIV reverse transcriptase and integrase. Bioorg Med Chem. 2010;18:4202-11 pubmed publisher
    ..Further SAR also demonstrated that optimal IN inhibition within our dual inhibitor scaffold requires a regiospecific (N-1) diketoacid (DKA)-carrying pendant with a certain length. ..
  37. Weber J, Vazquez A, Winner D, Rose J, Wylie D, Rhea A, et al. Novel method for simultaneous quantification of phenotypic resistance to maturation, protease, reverse transcriptase, and integrase HIV inhibitors based on 3'Gag(p2/p7/p1/p6)/PR/RT/INT-recombinant viruses: a useful tool in the multitarget era of anti. Antimicrob Agents Chemother. 2011;55:3729-42 pubmed publisher
  38. Gras G, Schneider M, Cavassini M, Lucht F, Loilier M, Verdon R, et al. Patterns of adherence to raltegravir-based regimens and the risk of virological failure among HIV-infected patients: the RALTECAPS cohort study. J Acquir Immune Defic Syndr. 2012;61:265-9 pubmed publisher
    ..05) were both independently associated with virological failure controlling for prior duration of viral suppression. Timely interdose intervals and high levels of adherence to raltegravir are both necessary to control HIV replication. ..
  39. Low A, Prada N, Topper M, Vaida F, Castor D, Mohri H, et al. Natural polymorphisms of human immunodeficiency virus type 1 integrase and inherent susceptibilities to a panel of integrase inhibitors. Antimicrob Agents Chemother. 2009;53:4275-82 pubmed publisher
    ..Most of the highly prevalent polymorphisms have little effect on InSTI susceptibility in the absence of specific primary mutations. Baseline testing for integrase susceptibility in InSTI-naïve patients is not currently warranted. ..
  40. Rangel H, Garzaro D, Fabbro R, Martinez N, Ossenkop J, Torres J, et al. Absence of primary integrase resistance mutations in HIV type 1-infected patients in Venezuela. AIDS Res Hum Retroviruses. 2010;26:923-6 pubmed publisher
    ..The availability of in-house assays allows for a more comprehensive surveillance of drug resistance to integrase inhibitors in Venezuela. ..
  41. Zolopa A, Berger D, Lampiris H, Zhong L, Chuck S, Enejosa J, et al. 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. 2010;201:814-22 pubmed publisher
    ..Elvitegravir was well-tolerated and produced rapid virologic suppression that was durable with active background therapy. Trial registration. identifier number: NCT00298350. ..
  42. Agrawal A, DeSoto J, Fullagar J, Maddali K, Rostami S, Richman D, et al. Probing chelation motifs in HIV integrase inhibitors. Proc Natl Acad Sci U S A. 2012;109:2251-6 pubmed publisher
    ..By isolating and examining the role of the MBG in a series of INSTIs, we have identified a scaffold (hydroxypyrones) that may provide access to a unique class of HIV-1 IN inhibitors, and may help overcome rising raltegravir resistance. ..
  43. Balakrishnan M, Yant S, Tsai L, O Sullivan C, Bam R, Tsai A, 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:e74163 pubmed publisher
  44. Ni X, Delelis O, Charpentier C, Storto A, Collin G, Damond F, et al. G140S/Q148R and N155H mutations render HIV-2 Integrase resistant to raltegravir whereas Y143C does not. Retrovirology. 2011;8:68 pubmed publisher
    ..Finally, the Y143C mutation counteracts the resistance conferred by the N155H mutation, probably accounting for the lack of detection of these mutations together in a single genome. ..
  45. Gottlieb G, Smith R, Dia Badiane N, Ba S, Hawes S, Toure M, et al. HIV-2 integrase variation in integrase inhibitor-naïve adults in Senegal, West Africa. PLoS ONE. 2011;6:e22204 pubmed publisher
    ..Emerging genotypic and phenotypic data suggest that HIV-2 is susceptible to the new class of HIV integrase inhibitors. We hypothesize that intrinsic HIV-2 integrase variation at "secondary" HIV-1 INI-resistance ..
  46. Telvekar V, Patel K. Pharmacophore development and docking studies of the hiv-1 integrase inhibitors derived from N-methylpyrimidones, Dihydroxypyrimidines, and bicyclic pyrimidinones. Chem Biol Drug Des. 2011;78:150-60 pubmed publisher
    ..The results obtained from our studies provide a valuable tool for designing of new lead molecules with potent activity. ..
  47. Suzuki S, Urano E, Hashimoto C, Tsutsumi H, Nakahara T, Tanaka T, et al. Peptide HIV-1 integrase inhibitors from HIV-1 gene products. J Med Chem. 2010;53:5356-60 pubmed publisher
    ..The addition of an octa-arginyl group to the inhibitory peptides caused a remarkable inhibition of the strand transfer and 3'-end-processing reactions catalyzed by IN and significant inhibition against HIV replication. ..
  48. Clavel F. HIV resistance to raltegravir. Eur J Med Res. 2009;14 Suppl 3:47-54 pubmed
  49. Mouscadet J, Delelis O, Marcelin A, Tchertanov L. Resistance to HIV-1 integrase inhibitors: A structural perspective. Drug Resist Updat. 2010;13:139-50 pubmed publisher
  50. Piralla A, Paolucci S, Gulminetti R, Comolli G, Baldanti F. HIV integrase variability and genetic barrier in antiretroviral naïve and experienced patients. Virol J. 2011;8:149 pubmed publisher
    ..Exposure to antivirals other than INI does not seem to significantly influence the emergence of mutations implicated in INI resistance. HIV-2 strain might have reduced susceptibility to INI. ..
  51. Desimmie B, Schrijvers R, Demeulemeester J, Borrenberghs D, Weydert C, Thys W, et al. LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions. Retrovirology. 2013;10:57 pubmed publisher
    ..LEDGINs thus profile as unique antivirals with combined early (integration) and late (IN assembly) effects on the HIV replication cycle. ..
  52. Brenner B, Lowe M, Moisi D, Hardy I, Gagnon S, Charest H, et al. Subtype diversity associated with the development of HIV-1 resistance to integrase inhibitors. J Med Virol. 2011;83:751-9 pubmed publisher
    ..These results demonstrate the importance of understanding subtype variability in the development of resistance to INIs. ..
  53. Moss D, Kwan W, Liptrott N, Smith D, Siccardi M, Khoo S, et al. Raltegravir is a substrate for SLC22A6: a putative mechanism for the interaction between raltegravir and tenofovir. Antimicrob Agents Chemother. 2011;55:879-87 pubmed publisher
    ..However, transport was limited compared to endogenous controls, and these transporters are unlikely to have a great impact on raltegravir pharmacokinetics. ..