Integrase-Inhibitor
Integrase inhibitors (integration ) inhibitors are virustatic acting drugs. These are drugs that inhibit the key enzyme integrase of retroviruses.
2005 began the first clinical trials after the development was slowed down to 2000 by a lack of suitable test methods and the high toxicity of some drugs. In 2000, the first time the principle of the strand transfer inhibition was uncovered. The compatibility seems to be good for a few weeks, but about long -term toxicity is not known. The same applies to the development of resistance. Cross-Class cross-resistance seem possible after initial laboratory data.
Effect
The integrase is next to reverse transcriptase and protease one of the three key enzymes in the replication cycle of HIV. The integrase is comprised of 288 amino acids and is encoded by the HIV pol gene. It is involved in the integration of viral DNA into the host DNA in the nucleus and is essential for the replication of HIV.
The integration of viral DNA proceeds through at least four steps. Each of these steps could be Inhibits theoretically. As with entry inhibitors are therefore potentially distinguish between different groups of active substances in the future.
Pyranodipyrimidine
Binding of the integrase enzyme in the cytoplasm to the viral DNA: The result is a so-called stable Präintegrationskomplex. Pyranodipyrimidine could integrase - DNA binding inhibitors can inhibit this step.
Prozessierungs inhibitors
In a first catalytic step, integrase separates out a dinucleotide at both ends of the viral DNA and then producing a new 3'- hydroxy termini within the pre-integration complex. Possible Prozessierungsinhibitoren are Styrylquinolone or Diketosäuren.
Strand transfer inhibitors ( STIs)
After the so- modified complex was introduced through the nuclear pore to the nucleus, binds the integrase to the host DNA. In this case, it provides for docking and irreversible binding of the viral DNA to the host DNA. This step is inhibited by the currently most developed integrase inhibitor raltegravir and elvitegravir.
Gap repair inhibitors
The combination of viral DNA and host cell DNA is a product with gaps, which is repaired by host cell's own repair enzymes. The repair can be inhibited, for example by methylxanthines.
Side effects
The most common (> 10 %) adverse events reported during clinical trials of currently known active compounds were diarrhea, nausea, headache and fever. The Therapieabruchrate due to adverse events was treated with raltegravir patients at two percent compared to 1.4 percent for placebo. Experiences from long-term treatment are not yet available.
Areas of application
They are used to combat the replication of a virus.
Agents
- Raltegravir
- Elvitegravir