Integrase inhibitors
DefinitionThis section has been translated automatically.
Antiretrovirally active substances that have the HIV enzyme integrase as their pharmacological starting point.
Note(s)This section has been translated automatically.
- Integrase is, along with reverse transcriptase and protease, one of the 3 key enzymes involved in the HIV-1 replication cycle and in the integration of viral DNA into the host DNA in the cell nucleus. Therefore the enzyme is essential for the replication of HIV. Furthermore, there is probably no integrase in human cells themselves. Therefore, integrase is an interesting pharmacological starting point for antiretrovirally active substances.
- The integration of viral DNA takes place in at least four steps, all of which can theoretically be inhibited by different (!) integrase inhibitors. Analogous to the entry inhibitors, it is therefore possible that in the future different groups of active substances will be distinguished.
- Binding of the integrase enzyme in the cytoplasm to the viral DNA: This results in a relatively stable so-called pre-integration complex. Pyranodipyrimidines, as integrase DNA binding inhibitors, can prevent this step.
- Processing: In a first catalytic step the integrase cuts out a dinucleotide at both ends of the viral DNA and produces new 3-hydroxyl ends within the pre-integration complex. So-called processing inhibitors are styrylquinolones or diketo acids.
- Strand transfer: After the pre-integration complex has been introduced into the cell nucleus through nuclear pores, the integrase binds to the host DNA. It mediates the docking and irreversible binding of the hydroxyl ends of the viral DNA to the phosphodiester bridges of the host DNA. This step is inhibited by the two currently most advanced integrase inhibitors, Raltegravir and Elvitegravir, known as strand transfer inhibitors (STIs).
- Gap repair: The combination of viral DNA and host cell DNA is an intermediate product with gaps that are repaired by host cell repair enzymes. Integrase may no longer be necessary, but repair can be inhibited by methylxanthines, for example.