Entry-Inhibitor
Entry inhibitors are drugs from the group of medicines called antivirals. You can inhibit ( interrupt ) the occurrence of certain viruses into the host cell. There are three key points in the admission process will underpin entry inhibitors:
- Binding of the virus to the receptor of the host cell (attachment inhibitor )
- Binding to co-receptors of the host cell ( co-receptor antagonists)
- Fusion with the host cell ( fusion inhibitors )
Effect
All of the following information relating to the HIV-1. According to their mode of action is different, the three categories of entry inhibitors:
Attachment inhibitors
The docking of the HIV glycoprotein gp120 to the CD4 receptor is the first step on entry into the cell. In theory, the docking procedure can be inhibited by different mechanisms. One possibility is the blocking of the CD4 receptor, the other of the gp120. Both possibilities are currently being investigated. As a result, the attachment inhibitors are divided again so that you can ensure in the medium term can not speak of a class of substances.
In the early 90s, was experimenting with CD4 molecules that prevent the attachment of HIV. Initial successes in the laboratory proved to a variety of reasons not clinically replicable. A new impetus in research on entry inhibitors with the development of the first clinically relevant representative of this group T- 20th Most new substances are not particularly well developed. Therefore, it is currently more concerned to demonstrate the principle in studies and to find drugs whose pharmacokinetics allows use in practice.
Currently in development substances contained:
TNX -355 is a monoclonal antibody. It binds to the CD4 receptor, thus preventing the entry of HIV. TNX -355 does not appear to inhibit the binding of gp120 to CD4, but rather that the binding of gp120 to the CCR5 and CXCR4 co-receptors. TNX -355 is developed by Tanox biosystem. TNX -355 may be administered intravenously. The first studies were carried out in 2004. In the meantime, are 48 - week data from a placebo-controlled phase II study. In the study, patients were administered in addition to ART TNX -335. The result was a significant and long-lasting vs. Virus waste. the control group.
A not yet finally clarified question is whether the functionality of CD4 cells is adversely affected by the active ingredient. So far, no adverse effects on the CD4 cells were detected. According to the manufacturer, there is an inverse correlation between the sensitivity of TNX -355 and soluble CD4. This suggests that TNX -355 - resistant viruses for soluble CD4 are hypersensitive.
BMS - 488 043 is an attachment inhibitor BMS of the company. It binds specifically and reversibly to gp120 of HIV and interfering with the binding to the CD4 cell. The first clinical results were published in 2004. Despite problems such as a very high number of tablets and expected, rapid development of resistance, the results are positive.
Coreceptor antagonists
HIV in addition to the CD4 receptor requires a co-receptor in order to be able to penetrate into the cell. Mid-90s, the two major co-receptors CXCR4 and CCR5 were detected.
HIV variants use CCR5 in addition to CD4 either - or CXCR4 receptors for cell entry. After this " Rezeptortropismus " are referred to HIV variants as R5 ( CCR5); Viruses with the use of CXCR4 are called X4 viruses. R5 viruses infect predominantly macrophages ( M -tropic viruses). X4 viruses primarily infect T cells (T -tropic viruses). Studies show that X4 viruses are associated with rapid CD4 cell waste and disease progression. Viruses both receptors are referred to as Dualtrope use. Moreover, there are mixed populations of R5 and X4 viruses. In the early stages of infection are often dominated by R5 viruses, and later the more virulent X4 viruses.
Depending on the starting point to CCR5 and CXCR4 antagonists can be distinguished. They block the respective coreceptor. The development of the CCR5 antagonist is more advanced than that of the CXCR4 antagonist.
Due to the selective pressure of unilateral suppression of R5 viruses ( with mixed populations), it is expected to lead to a shift in favor of X4 viruses. It is currently believed that this, however, " creates" no X4 viruses. In a clinical study with maraviroc, there was - in spite of the shifting effect - even to an increase in CD4 cells compared with the placebo treatment.
Fears that the blockade of the CCR5 receptor could have other consequences are contradicted by the fact that people with a corresponding defect are perfectly healthy. Even the fear of autoimmune reactions by docking, could not be confirmed in animal experiments. In an analysis of all Phase I - II trials of maraviroc no negative effects on immune functions were observed.
Reports of tumor diseases (mostly malignant lymphoma) in a study with vicriviroc, rather give cause for concern. In other studies, this accumulation was not observed.
Fusion inhibitors
Fusion inhibitors prevent the entry of HIV into the immune cells by blocking the merging of the viral envelope with the cell membrane.
Side effects
Previously available substances associated with moderate side effects. Due to the significant heterogeneity observed no global statement for all entry inhibitors can meet. The future will show whether drugs with new approaches are similarly well tolerated within the group of substances.
Areas of application
They are used to fight viruses. So far, there are drugs against HIV.
Resistance
Theoretically, even with entry inhibitors, the risk of resistance developing. Laboratory tests also include Cross-Class cross-resistance is not sufficient. However, there are on this subject so far no human studies.
Agents
- Enfuvirtide
- Maraviroc