Entry inhibitor

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Entry inhibitors are drugs from the group of antivirals . They inhibit (interrupt) the entry of certain viruses into the host cell . There are three key points in the entry process where entry inhibitors apply:

  • Binding of the virus to the host cell's receptor (attachment inhibitors)
  • Binding to coreceptors of the host cell (coreceptor antagonists)
  • Fusion with the host cell (fusion inhibitors)

effect

All information below relates to HIV-1. The three groups of entry inhibitors are distinguished according to their mode of action:

Attachment inhibitors

The docking of the HIV glycoprotein gp120 on the CD4 receptor is the first step in entering the cell. In theory, the docking process can be inhibited by various mechanisms. One possibility is to block the CD4 receptor, the other that of the gp120. Both options are currently being investigated. As a result, the attachment inhibitors are subdivided again, so that in the medium term one certainly cannot speak of a substance class.

As early as the early 1990s, experiments were made with CD4 molecules that prevent HIV from docking. Initial successes in the laboratory have not been shown to be clinically replicable for a variety of reasons. Research on entry inhibitors received a new impetus with the development of the first clinically relevant representative of this group, T-20. Most of the new substances are not very well developed. Therefore, it is currently more a matter of proving the principle in studies and finding active ingredients whose pharmacokinetics allow their use in practice.

Substances currently under development:

TNX-355 is a monoclonal antibody . It binds directly to the CD4 receptor and thus prevents the entry of HIV. TNX-355 does not seem to prevent the binding of gp120 to CD4, but rather the binding of gp120 to the co-receptors CCR5 and CXCR4 . TNX-355 is developed by Tanox Biosystem . TNX-355 can only be administered intravenously. The first studies were carried out in 2004. 48-week data from a placebo-controlled phase II study are now available. As part of the study, patients were given TNX-335 in addition to ART. The result was a clear and long-lasting virus drop versus. the control group.

A question that has not yet been finally clarified is whether the functionality of the CD4 cells is impaired by the active substance. So far, no negative effects on the CD4 cells have been found. According to the manufacturer, there is an inverse correlation between the sensitivity for TNX-355 and soluble CD4. This suggests that TNX-355 resistant viruses become hypersensitive to soluble CD4.

BMS-488043 is an attachment inhibitor from BMS. It binds specifically and reversibly to gp120 of HIV and prevents it from docking on the CD4 cell. The first clinical results were published in 2004. Despite problems such as a very high number of tablets and the expected rapid development of resistance, the results are positive.

Coreceptor antagonists

In addition to the CD4 receptor, HIV needs a coreceptor in order to be able to penetrate the cell. In the mid-1990s, the two most important coreceptors CXCR4 and CCR5 were discovered.

In addition to CD4, HIV variants use either CCR5 or CXCR4 receptors for cell entry. According to this “receptor tropism”, HIV variants are referred to as R5 (CCR5); Viruses that use CXCR4 are called X4 viruses. R5 viruses mainly infect macrophages ( M-trope viruses). X4 viruses mainly infect T cells ( T-tropic viruses). Studies show that X4 viruses are associated with rapid CD4 cell decline and disease progression. Viruses that use both receptors are called dual tropics . There are also mixed populations of R5 and X4 viruses. R5 viruses are mostly found in the early stages of infection, later the more virulent X4 viruses.

Depending on the starting point, a distinction can be made between CCR5 and CXCR4 antagonists. They block the respective coreceptor. The development of CCR5 antagonists is more advanced than that of the CXCR4 antagonists.

The selection pressure of one-sided suppression of R5 viruses (in mixed populations) is likely to lead to a shift in favor of the X4 viruses. It is currently assumed that this will not "create" any X4 viruses. In a clinical study with maraviroc, despite the shifting effect, there was even an increase in CD4 cells compared to placebo treatment.

Fears that blocking the CCR5 receptor could have other consequences are refuted by the fact that people with a corresponding defect are completely healthy. The fear of autoimmune reactions caused by docking could also not be confirmed in animal experiments. An analysis of all Phase I-II studies with maraviroc found no adverse effects on immune function.

Reports of tumor diseases (mostly malignant lymphomas) in a study with vicriviroc are more of a cause for concern. This frequency was not observed in other studies.

Fusion inhibitors

Fusion inhibitors prevent HIV from entering the immune cells by blocking the fusion of the virus envelope with the cell membrane.

Side effects

So far available substances are associated with moderate side effects. Due to the clear heterogeneity, no global statement can be made for all entry inhibitors. The future will show whether active ingredients with new approaches within the substance group are also tolerated just as well.

application areas

They are used to fight viruses. So far, active substances against HIV exist .

Resistances

Theoretically, there is also a risk of resistance developing with entry inhibitors. Laboratory tests do not rule out cross-resistance across classes. However, there are no human studies on this topic to date.

Active ingredients

literature

Attachment inhibitors

  • D Norris, J Morales, E Godofsky et al .: TNX-355, in combination with optimized background regimen, achieves statistically significant viral load reduction and CD4 cell count increase when compared with OBR alone in phase 2 study at 48 weeks . Abstr. ThLB0218, XVI IAC 2006, Toronto
  • T. Duensing, M. Fung, S. Lewis, S. Weinheimer: In vitro characterization of HIV isolated from patients treated with the entry inhibitor TNX-355 . Abstract 158 ​​LB, 13th CROI 2006, Denver.
  • J. Kadow, HG. Wang, PF. Lin: Small-molecule HIV-1 gp120 inhibitors to prevent HIV-1 entry: an emerging opportunity for drug development . In: Curr Opin Investig Drugs , 2006, 7, pp. 721-726. PMID 16955683

Coreceptor antagonists

  • S. Abel, D. Russell, C. Ridgway, G. Muirhead: Overview of the drug-drug interaction data for maraviroc . Abstract 76, 7th IWCPHT 2005, Quebec.
  • S. Abel, R. Taylor-Worth, C. Ridgway, G. Weissgerber, M. Kraft: Effect of boosted tipranavir on the pharmacokinetics of maraviroc (UK427,857) in healthy volunteers . Abstract 77, 7th IWCPHT 2006, Lisbon.
  • F. Giguel, L. Beebe, TS. Migone, D. Kuritzkes: The anti-CCR5 mAb004 inhibits hiv-1 replication synergistically in combination with other antiretroviral agents but does not select for resistance during in vitro passage . Abstract 505, 13th CROI 2006, Denver.
  • W. Greaves, R. Landovitz, G. Fatkenheuer et al .: Late virologic breakthrough in treatment naive patients on a regimen of combivir + vicriviroc . Abstract 161LB, 13th CROI 2006, Denver.
  • R. Gulick, Z. Su, C. Flexner et al .: ACTG 5211: phase 2 study of the safety and efficacy of vicriviroc in HIV-infected treatment-experienced subjects . Abstract ThLB0217, XVI IAC 2006, Toronto.
  • W. Huang, J. Toma, S. Fransen, et al .: Modulation of HIV-1 co-receptor tropism and susceptibility to co-receptor inhibitors by regions outside of the V3 Loop: Effect of gp41 amino acid substitutions . Abstract H-245, 46th ICAAC 2006, San Francisco.
  • H. Mayer, E. van der Ryst, M. Saag et al .: Safety and efficacy of maraviroc, a novel CCR5 antagonist, when used in combination with optimized background therapy for the treatment of antiretroviral-experienced subjects infected with dual / mixed- tropic HIV-1: 24-week results of a phase 2b exploratory trial . Abstract ThLB0215, XVI IAC 2006, Toronto.
  • M. Mosley, C. Smith-Burchnell, J. Mori et al .: Resistance to the CCR5 antagonist maraviroc is characterized by dose-response curves that display a reduction in maximal inhibition . Abstract 598, 13th CROI 2006, Denver.
  • W. Olson, H. Doshan, C. Zhan et al .: First-in-humans trial of PRO 140, a humanized CCR5 monoclonal antibody for HIV-1 therapy . Abstract WePe6.2C04, 3rd IAS 2005, Rio de Janeiro.
  • WC. Olson, H. Doshan, C. Zhan: Prolonged coating of CCR5 lymphocytes by PRO 140, a humanized CCR5 monoclonal antibody for HIV-1 therapy . Abstract 515, 13th CROI 2006, Denver.
  • C. Peters, T. Kawabata, P. Syntin et al .: Assessment of immunotoxic potential of maraviroc in cynomolgus monkeys . Abstract 1100, 45th ICAAC 2005, Washington.
  • HM. Steel: Special presentation on aplaviroc-related hepatotoxicity . 10th EACS 2005, Dublin.
  • Y. Tanaka, K. Okuma, R. Tanaka et al .: Development of novel orally bioavailable CXCR4 antagonist, KRH-3955 and KRH-3140: binding specificity, pharmacokinetics and anti-HIV activity in vivo and in vitro . Abstract 49 LB, 13th CROI 2006, Denver.
  • CL. Tremblay, F. Giguel, TC. Chou et al .: TAK-652, a novel small molecule inhibitor of CCR5 has favorable anti-HIV interactions with other antiretrovirals in vitro . Abstract 542, 12th CROI 2005, Boston.
  • X. Wang, S. Douglas, JP. Lai et al .: Neurokinin-1 receptor antagonist inhibits drug-resistant HIV-1 infection of monocyte-derived macrophages in vitro . Abstract 511, 13th CROI 2006, Denver.
  • T. Wilkin, Z. Su, D. Kuritzkes et al .: Co-receptor tropism in patients screening for ACTG 5211, a phase 2 study of vicriviroc, a CCR5 inhibitor . Abstract 655, 13th CROI 2006, Denver.
  • A. Ayoub, E. van der Ryst, K. Turner, M. McHale: A review of the markers of immune function during the maraviroc phase 1 and 2a studies . Abstract 509, 14th CROI 2007, Los Angeles.
  • M. Baba, H. Miyake, X. Wang, M. Okamotoand, K. Takashima: Isolation and Characterization of human immunodeficiency virus type 1 resistant to the small-molecule CCR5 antagonist TAK-652 . In: Antimicrob Agents Chemother , 2006 Nov 20. PMID 17116673
  • M. Baba, K. Takashima, H. Miyake et al .: TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in vitro and has favorable pharmacokinetics in humans . In: Antimicrob Agents Chemother , 2005, 49, pp. 4584-4591. PMID 16251299
  • V. Briz, E. Poveda, V. Soriano: HIV entry inhibitors: mechanisms of action and resistance pathways . In: J Antimicrob Chemother , 2006, 57, pp. 619-627. PMID 16464888
  • ZL. Brumme, J. Goodrich, HB. Mayer et al .: Molecular and clinical epidemiology of CXCR4-using HIV-1 in a large population of antiretroviral-naive individuals . J Infect Dis 2005, 192, pp. 466-474. PMID 15995960
  • G. Fatkenheuer, AL. Pozniak, MA. Johnson et al .: Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1 . In: Nat Med , 2005, 11, pp. 1170-1172. PMID 16205738
  • J. Lalezari, J. Godrich, E. DeJesus et al .: Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1: 24-week results of a phase 2b / 3 study in the US and Canada . Abstract 104LB, 14th CROI 2007, Los Angeles.
  • GJ. Moyle, A. Wildfire, S. Mandalia et al. :: Epidemiology and predictive factors for chemokine receptor use in HIV-1 infection . In: J Infect Dis , 2005, 191, pp. 866-872. PMID 15717260
  • G. Moyle, DeJesus E, M. Boffito et al .: CXCR4 antagonism: proof of activity with AMD 11070 . Abstract 511, 14th CROI 2007, Los Angeles.
  • JD. Murga, M. Franti, DC. Pevear, PJ. Maddon, toilet. Olson: Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1 . In: Antimicrob Agents Chemother , 2006, 50, pp. 3289-3296. PMID 17005807
  • M. Nelson, G. Fätkenheuer, I. Konourina et al .: Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia and North America: 24 week results . Abstract 104aLB, 14th CROI 2007, Los Angeles.
  • PA Pugach, JT Marozsan, JE Ketas, LJ Landes, PS Moore, E. Kuhmann: HIV-1 clones resistant to a small molecule CCR5 inhibitor use the inhibitor-bound form of CCR5 for entry . In: Virology , 361, 2007, pp. 212-228, PMID 17166540 PMC 189219 (free full text).
  • M. Saag, S. Rosenkranz, S. Becker et al .: Proof of concept aof ARV activity of AMD 11070 (an orally administered CXCR4 entry inhibitor: results of the first dosing cohort A studied in ACTG protocol A5210) . Abstract 512, 14th CROI 2007, Los Angeles.
  • JM. Strizki, C. Tremblay, S. Xu et al .: Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1 . In: Antimicrob Agents Chemother , 2005, 49, pp. 4911-4919. PMID 16304152
  • M. Westby, M. Lewis, J. Whitcomb et al .: Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir . In: J Virol , 2006, 80, pp. 4909-4920. PMID 16641282
  • MC Westby, Smith-Burchnell, JM Mori, M. Lewis, M. Mosley, P. Stockdale, G. Dorr, M. Ciaramella Perros: Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor -bound receptor for entry . In: J. Virol. , 81, 2007, pp. 2359-2371, PMID 17182681 , PMC 186594 (free full text).
  • R. Wong, V. Bodard, M. Metz et al .: Understanding the interactions between CXCR4 and AMD 11070, a first-in-class small-molecule antagonist of the HIV coreceptor . Abstract 495, 14th CROI 2007, Los Angeles.

Fusion inhibitors

  • M. Delmedico, B. Bray, N. Cammack et al .: Next generation HIV peptide fusion inhibitor candidates achieve potent, durable suppression of virus replication in vitro and improved pharmacokinetic properties . Abstract 48, 13th CROI 2006, Denver.
  • S. Jiang, H. Lu, S. Liu et al .: Small molecule HIV entry inhibitors targeting gp41 . Abstract TuOa0201. 3rd IAS 2005, Rio de Janeiro.
  • SJ. Dai, GF. Dou, XH. Qiang et al .: Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in monkeys and its inhibitory concentration in vitro . In: Acta Pharmacol Sin , 2005, 26, pp. 1274-1280. PMID 16174446
  • S. Jiang, H. Lu, S. Liu, Q. Zhao, Y. He, AK. Debnath: N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion . In: Antimicrob Agents Chemother , 2004, 48, pp. 4349-4359. PMID 15504864

Individual evidence

  1. ↑ ES Daar, XL Li, T Moudgil, DD. Ho: High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates . In: Proc Natl Acad Sci USA , 1990, 87, pp. 6574-6578. PMID 2395859
  2. ↑ RT Schooley, TC Merigan, P Gaut et al .: Recombinant soluble CD4 therapy in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex . In: Ann Intern Med , 1990, 112, pp. 247-253. hPMID 2297203
  3. ↑ JM Jacobson, DR Kuritzkes, E Godofsky et al .: Phase 1b study of the anti-CD4 monoclonal antibody TNX-355 in HIV-infected subjects: safety and antiretroviral activity of multiple doses . Abstract 536, 11th CROI 2004, San Francisco.
  4. ↑ DR Kuritzkes, J Jacobson, WG Powderly et al .: Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1 . In: J Infect Dis , 2004, 189, pp. 286-291. PMID 14722894 .
  5. ↑ Norris 2006
  6. ^ T Duensing, M Fung, S Lewis, S. Weinheimer: In vitro characterization of HIV isolated from patients treated with the entry inhibitor TNX-355 . Abstract 158 ​​LB, 13th CROI 2006, Denver.
  7. ↑ G Hanna, L Lalezari, J Hellinger et al .: Antiviral activity, safety, and tolerability of a novel, oral small-molecule HIV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects . Abstract 141, 11th CROI, 2004, San Francisco.
  8. ↑ RI Connor, KE Sheridan, D Ceradini, S Choe, NR. Landau: Change in coreceptor use coreceptor use correlates with disease progression in HIV-1 - infected individuals . In: J Exp Med , 1997, 185, pp. 621-628. PMID 9034141
  9. ^ M Westby, M Lewis, J Whitcomb et al .: Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir . In: J Virol , 2006, 80, pp. 4909-4920, PMID 16641282 .
  10. ↑ H Mayer, E van der Ryst, M Saag et al .: Safety and efficacy of maraviroc, a novel CCR5 antagonist, when used in combination with optimized background therapy for the treatment of antiretroviral-experienced subjects infected with dual / mixed-tropic HIV -1: 24-week results of a phase 2b exploratory trial . Abstract ThLB0215, XVI IAC 2006, Toronto.
  11. ↑ C Peters, T Kawabata, P Syntin et al .: Assessment of immunotoxic potential of maraviroc in cynomolgus monkeys . Abstract 1100, 45th ICAAC 2005, Washington.
  12. ^ A Ayoub, E van der Ryst, K Turner, M. McHale: A review of the markers of immune function during the maraviroc phase 1 and 2a studies . ( Memento of August 7, 2008 in the Internet Archive ) Abstract 509, 14th CROI 2007, Los Angeles.
  13. ^ R Gulick, Z Su, C Flexner et al .: ACTG 5211: phase 2 study of the safety and efficacy of vicriviroc in HIV-infected treatment-experienced subjects . Abstract ThLB0217, XVI IAC 2006, Toronto.