Skip to main content
SpringerLink
Log in

HIV-1 Integrase Inhibitors

An Emerging Clinical Reality

  • Review Article
  • Published:
Drugs in R & D Aims and scope Submit manuscript

Abstract

From the discovery of HIV-1 integrase (IN) inhibitors using enzyme-based assays in 1992, it has taken 15 years to achieve success in human clinical trials. Currently available antiretroviral drugs set high clinical standards in efficacy and long-term safety for upcoming novel HIV/AIDS therapeutic agents. The results from advanced stages of human clinical trials with IN inhibitors indicate a promising future for these compounds as a novel class of antiretroviral drugs. Success and failure of previously discovered antiretroviral drugs have taught us that there are no magic bullets in eradicating HIV. However, approval of drugs selectively targeting IN has long been awaited. There is once again a surge of interest in the field focusing on clinical development of IN inhibitors. Here, we summarise the current status of IN inhibitors under clinical development. These agents include S-1360, GSK-364735, L-870,810, L-870,812, MK-0518, GS-9137, L-900564, GS-9224, and BMS-707035. Promising antiviral activity has already been achieved with MK-0518 and GS-9137 in late-stage clinical studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I
Fig. 2

Similar content being viewed by others

Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Chun TW, Finzi D, Margolick J, et al. In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med 1995; 1 (12): 1284–90

    Article  PubMed  CAS  Google Scholar 

  2. Saksena NK, Potter SJ. Reservoirs of HIV-1 in vivo: implications for antiretroviral therapy. AIDS Rev 2003; 5 (1): 3–18

    PubMed  Google Scholar 

  3. Potter SJ, Dwyer DE, Saksena NK. Differential cellular distribution of HIV-1 drug resistance in vivo: evidence for infection of CD8+ T cells during HAART. Virology 2003; 305 (2): 339–52

    Article  PubMed  CAS  Google Scholar 

  4. Potter SJ, Lemey P, Dyer WB, et al. Genetic analyses reveal structured HIV-1 populations in serially sampled T lymphocytes of patients receiving HAART. Virology 2006; 348 (1): 35–46

    Article  PubMed  CAS  Google Scholar 

  5. Wainberg MA, Sawyer JP, Montaner JS, et al. Challenges for the clinical development of new nucleoside reverse trans-criptase inhibitors for HIV infection. Antivir Ther 2005; 10 (1): 13–28

    PubMed  CAS  Google Scholar 

  6. Yusa K, Harada S. Acquisition of multi-PI (protease inhibitor) resistance in HIV-1 in vivo and in vitro. Curr Pharm Des 2004; 10 (32): 4055–64

    Article  PubMed  CAS  Google Scholar 

  7. Shet A, Berry L, Mohri H, et al. Tracking the prevalence of transmitted antiretroviral drug-resistant HIV-1: a decade of experience. J Acquir Immune Defic Syndr 2006; 41 (4): 439–46

    Article  PubMed  Google Scholar 

  8. Shet A, Markowitz M. Transmitted multidrug resistant HIV-1: new and investigational therapeutic approaches. Curr Opin Investig Drugs 2006; 7 (8): 709–20

    PubMed  CAS  Google Scholar 

  9. Brown PO. Integration: In: Coffin J, Hughes SH, Varmus, HE, editors. Retroviruses. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 1997: 161-203

  10. Bushman FD, Craigie R. Activities of human immuno-deficiency virus (HIV) integration protein in vitro: specific cleavage and integration of HIV DNA. Proc Natl Acad Sci U S A 1991; 88 (4): 1339–43

    Article  PubMed  CAS  Google Scholar 

  11. Neamati N. Patented small molecule inhibitors of HIV-1 integrase: a 10-year saga. Expert Opin Ther Pat 2002; 12 (5): 709–24

    Article  CAS  Google Scholar 

  12. Dayam R, Neamati N. Small-molecule HIV-1 integrase inhibitors: the 2001–2002 update. Curr Pharm Des 2003; 9 (22): 1789–802

    Article  PubMed  CAS  Google Scholar 

  13. Pommier Y, Johnson AA, Marchand C. Integrase inhibitors to treat HIV/AIDS. Nat Rev Drug Discov 2005; 4 (3): 236–48

    Article  PubMed  CAS  Google Scholar 

  14. Dayam R, Deng J, Neamati N. HIV-1 integrase inhibitors: 2003–2004 update. Med Res Rev 2006; 26 (3): 271–309

    Article  PubMed  CAS  Google Scholar 

  15. Savarino A. A historical sketch of the discovery and development of HIV-1 integrase inhibitors. Expert Opin Investig Drugs 2006; 15 (12): 1507–22

    Article  PubMed  CAS  Google Scholar 

  16. 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

    Article  PubMed  CAS  Google Scholar 

  17. Yoshinaga T, Fujishita SA, Fujishita T, et al. In vitro activity of a new HIV-1 integrase inhibitor in clinical development. In: 9th Conference on Retroviruses and Opportunistic Infections; 2002 February 24–28; Seattle, WA 2002

    Google Scholar 

  18. Billich A. S-1360 Shionogi-GlaxoSmithKline. Curr Opin Investig Drugs 2003; 4 (2): 206–9

    PubMed  CAS  Google Scholar 

  19. Fikkert V, Hombrouck A, Van Remoortel B, et al. Multiple mutations in human immunodeficiency virus-1 integrase confer resistance to the clinical trial drug S-1360. AIDS 2004; 18 (15): 2019–28

    Article  PubMed  CAS  Google Scholar 

  20. Rosemond MJ, St John-Williams L, Yamaguchi T, et al. 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 2004; 147 (2): 129–39

    Article  PubMed  CAS  Google Scholar 

  21. Reddy S, Min S, Borland J, et al. A double-blind, parallel, single and repeat dose-escalation study to investigate the safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor GSK364735 in healthy subjects (GRZ105655). In: 14th Conference on Retroviruses and Opportunistic Infections; 2007 Feb 25–28; Los Angeles (CA)

    Google Scholar 

  22. Trial identifier: NCT00398125; official title: A phase 2a, multicenter, randomized, parallel, double-blind, dose ranging, pla-cebo-controlled study to compare antiviral effect, safety, toler-ability and pharmacokinetics of GSK364735 monotherapy versus placebo over 10 days in HIV-1 infected adults [online]. Available from http://www.clinicalTrials.gov [Accessed 2007 Mar 8]

  23. Zhuang L, Wai JS, Embrey MW, et al. 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 2003; 46 (4): 453–6

    Article  PubMed  CAS  Google Scholar 

  24. Petrocchi A, Koch U, Matassa VG, et al. From dihydroxypyrimidine carboxylic acids to carboxamide HIV-1 integrase inhibitors: SAR around the amide moiety. Bioorg Med Chem Lett 2007; 17 (2): 350–3

    Article  PubMed  CAS  Google Scholar 

  25. Young S. L-870,810: A potent antiviral HIV integrase inhibitor with potential clinical utility. In: The XIV International AIDS conference; 2002 Jul 7–12; Barcelona, Spain

    Google Scholar 

  26. Hazuda DJ, Anthony NJ, Gomez RP, et al. A naphthyridine carboxamide provides evidence for discordant resistance be-tween mechanistically identical inhibitors of HIV-1 integrase. Proc Natl Acad Sci U S A 2004; 101 (31): 11233–8

    Article  PubMed  CAS  Google Scholar 

  27. Little S, Drusano G, Schooley R, et al. Antiviral effect of L-000870810, a novel HIV-1 integrase inhibitor, in HIV-1 infected patients. In: 12th Conference on Retroviruses and Opportunistic Infections; 2005 Feb 22–25; Boston (MA)

    Google Scholar 

  28. Egbertson MS, Moritz HM, et al. A potent and orally active HIV-1 integrase inhibitor. Bioorg Med Chem Lett 2007; 17 (5): 1392–8

    Article  PubMed  CAS  Google Scholar 

  29. Hazuda DJ, Young SD, Guare JP, et al. Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques. Science 2004; 305 (5683): 528–32

    Article  PubMed  CAS  Google Scholar 

  30. Miller M, Witmer M, Stillmock K, et al. Biochemical and antiviral activity of MK-0518, a potent HIV integrase inhibitor. In: XVI International AIDS Conference; 2006 August 13–18; Toronto, Canada

    Google Scholar 

  31. Low A, Mohri H, Markowitz M. Frequency of naturally occurring polymorphisms associated with resistance to integrase inhibitors in a recently infected cohort. In: 14th Conference on Retroviruses and Opportunistic Infections; 2007 Feb 25–28; Los Angeles (CA)

    Google Scholar 

  32. Petry A, Wenning LA, Laethem M, et al. Safety, tolerability, and pharmacokinetics after single and multiple doses of MK-0518 in healthy subjects. In: 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2006 Sep 27–30; San Francisco (CA)

    Google Scholar 

  33. Kassahun K, MCIntosh I, Hreniuk D, et al. Absorption, metabolism and excretion of MK-0518, a potent HIV-1 integrase inhibitor, in healthy male volunteers. In: 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2006 Sep 27–30; San Francisco (CA)

    Google Scholar 

  34. Markowitz M, Morales-Ramirez JO, Nguyen BY, et al. 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 2006; 43 (5): 509–15

    Article  PubMed  CAS  Google Scholar 

  35. Morales-Ramirez JO, Teppler H, Kovacs C, et al. MK-0518, the first integrase inhibitor for HIV, no blarney. In: 10th European AIDS Conference; 2005 Nov 17–20; Dublin, Ireland

    Google Scholar 

  36. Markowitz M, Nguyen B-Y, Gotuzzo F, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients. In: XVI International AIDS Conference; 2006 Aug 13–18; Toronto, Canada

    Google Scholar 

  37. Grinsztejn B, Nguyen B-Y, Katlama C, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. In: 13th Conference on Retroviruses and Opportunistic Infections; 2006 Feb 5–8; Denver (CO)

    Google Scholar 

  38. Grinsztejn B, Nguyen B-Y, Katlama C, et al. A novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus: 24 week data. In: 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2006 Sep 27–30; San Francisco (CA)

    Google Scholar 

  39. Trial identifier: NCT00369941; official title: A multicenter, double-blind, randomized, active-controlled study to evaluate the safety and antiretroviral activity of MK0518 versus efavirenz in treatment naive HIV-infected patients, each in combination with TRUVADA™ [online]. Available from http://www.clinicalTrials.gov [Accessed 2007 Apr 4]

  40. Trial identifier: NCT00377065; official title: Early access of MK0518 in combination with an optimized background antire-troviral therapy (OBT) in highly treatment experienced HIV-1 infected patients with limited to no treatment options [online]. Available from http://www.clinicalTrials.gov [Accessed 2007 Mar 6]

  41. Cooper D, Gatell J, Rockstroh J, et al. Results of BENCHMRK-1, a Phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. In: 14th Conference on Retroviruses and Opportunistic Infections; 2007 Feb 25–28; Los Angeles (CA)

    Google Scholar 

  42. Steigbigel R, Kumar P, Eron J, et al. Results of BENCHMRK-2, a Phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. In: 14th Conference on Retroviruses and Opportunistic Infections; 2007 Feb 25–28; Los Angeles (CA)

    Google Scholar 

  43. Wai J, Fisher T, Embrey M, et al. Next generation of inhibitors of HIV-1 integrase strand transfer inhibitor: structural diversity and resistance profiles. In: 14th Conference on Retroviruses and Opportunistic Infections; 2007 Feb 25–28; Los Angeles (CA)

    Google Scholar 

  44. Sato M, Motomura T, Aramaki H, et al. Novel HIV-1 integrase inhibitors derived from quinolone antibiotics. J Med Chem 2006; 49 (5): 1506–8

    Article  PubMed  CAS  Google Scholar 

  45. DeJesus E, Berger D, Markowitz M, et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treat-ment-experienced patients. J Acquir Immune Defic Syndr 2006; 43 (1): 1–5

    Article  PubMed  CAS  Google Scholar 

  46. Matsuzaki Y, Watanabe W, Yamataka K, et al. JTK-303/GS 9137, a novel small-molecule inhibitor of HIV-1 integrase: anti-HIV activity profile and pharmacokinetics in animals. In: 13th Conference on Retroviruses and Opportunistic Infections; 2006 Feb 5–8; Denver (CO)

    Google Scholar 

  47. Ramanathan S, Skillington J, Plummer A, et al. Lack of clinically relevant drug-drug interaction between ritonavir-boosted GS-9137 (GS-9137/r) and emtricitabine (FTC)/ tenofovir dis-oproxil fumarate (TDF). In: XVI International AIDS Confer-ence; 2006 Aug 13–18; Toronto, Canada

    Google Scholar 

  48. Ramanathan S, Lagan K, Plummer A, et al. Lack of clinically relevant drug-drug interaction between the ritonavir-boosted HIV integrase inhibitor GS-9137/r and zidovudine (ZDV). In: XVI International AIDS Conference; 2006 Aug 13–18; Toronto, Canada

    Google Scholar 

  49. Kodama E, Shimura K, Sakagami Y, et al. In vitro antiviral activity and resistance profile of a novel HIV integrase inhibitor JTK-303/GS-9137. In: 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2006 Sep 27–30; San Francisco (CA)

    Google Scholar 

  50. Jones G, Ledford R, Yu F, et al. Resistance profile of HIV-1 mutants in vitro selected by the HIV-1 integrase inhibitor, GS-9137 (JTK-303). In: 14th Conference on Retroviruses and Opportunistic Infections; 2007 Feb 25–28; Los Angeles (CA)

    Google Scholar 

  51. Kawaguchi I, Ishikawa T, Ishibashi M, et al. Safety and pharmacokinetics of single oral dose of JTK-303/GS 9137, a novel HIV integrase inhibitor, in healthy volunteers. In: 13th Conference on Retroviruses and Opportunistic Infections; 2006 Feb 5–8; Denver (CO)

    Google Scholar 

  52. DeJesus E, Berger D, Markowitz M, et al. The HIV integrase inhibitor GS-9137 (JTK-303) exhibits potent antiviral activity in treatment-naive and experienced patients. In: 13th Confer-ence on Retroviruses and Opportunistic Infections; 2006 Feb 5–8; Denver (CO)

    Google Scholar 

  53. Zolopa A, Mullen M, Berger D, et al. The HIV integrase inhibitor GS-9137 demonstrates potent ARV activity in treat-ment-experienced patients. In: 14th Conference on Re-troviruses and Opportunistic Infections; 2007 Feb 25–28; Los Angeles (CA)

    Google Scholar 

  54. Trial identifier: NCT00397566; official title: Randomized, placebo-controlled, ascending multiple dose study to evaluate the safety, pharmacokinetics, and pharmacodynamics of BMS-707035 in HIV-1 infected subjects [online]. Available from http://www.clinicalTrials.gov [Accessed 2007 Mar 7]

  55. Goldgur Y, Dyda F, Hickman AB, et al. Three new structures of the core domain of HIV-1 integrase: an active site that binds magnesium. Proc Natl Acad Sci U S A 1998; 95 (16): 9150–4

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from The Campbell Foundation and the Universitywide AIDS Research Program to Nouri Neamati. The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA, 90089, USA

    Raveendra Dayam, Laith Q. Al-Mawsawi &  Nouri Neamati

Authors
  1. Raveendra Dayam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laith Q. Al-Mawsawi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nouri Neamati
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nouri Neamati.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dayam, R., Al-Mawsawi, L.Q. & Neamati, N. HIV-1 Integrase Inhibitors. Drugs R D 8, 155–168 (2007). https://doi.org/10.2165/00126839-200708030-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00126839-200708030-00003

Keywords

Search

Navigation