Integrase Inhibitors

When HIV enters a cell it carries with it three viral enzymes essential to it's replication.

  1. Reverse transcriptase synthesizes a double helix HIV DNA chain from the single strand viral RNA template.
  2. Integrase has four known functions:
    1. It prepares the viral DNA for integration into the host DNA.
    2. It transports the viral DNA through a nuclear pore
    3. It cleaves specific regions on the host DNA.
    4. It inserts the viral DNA segment.
  3. Protease acts in the host cytoplasm to cleave long viral polypeptide chains. The resulting shorter glycoproteins accumulated at the cell membrane. When requisite components are aggregated, the assembly buds and separates from the host. Once separated, protease acts again to cleave the enveloped glycoproteins into active viral components and the virus becomes infectious.

There are currently three FDA approved Intergrase inhibitors, raltegravir, elvitegravir and dolutegravir. Raltegravir, elvitegravir and dolutegravir are integrase strand transfer inhibitors (InSTIs). InSTIs act by chelating the metallic cationic cofactors, either Mn2+-or Mg2+, on integrase molecule. Without the active metallic cationic cofactors, integrase cannot attach to and bind to the host DNA thereby blocking transfer of the strand of viral DNA into the host DNA.

InSTIs are not approved to be used as a monotherapy. Raltegravir, elvitegravir and dolutegravir are approved to be used as part of combination antiretroviral therapy. There is no human equlvalent of integrase and blocking integrase activity has resulted in few significant side effects.