Flavopiridol inhibits cellular processes essential to replication of HIV
Paul Blanchard, HIV i-Base
Research published in the Journal of Biological Chemistry suggests that flavopiridol, a drug already undergoing clinical trials as a cancer treatment, may also have potential as an anti-HIV therapy. A team at the University of California, San Francisco, discovered that very low concentrations of flavopiridol blocked HIV-1 replication in cell culture experiments.
Flavopiridol is a novel semisynthetic flavone which was first isolated from an Indian plant source in the Hoechst Research Centre, Mumbai, India. Hoechst has subsequently merged with Rhone-Poulenc to create Aventis Pharma a multinational company with a strong presence in Germany (headquarters in Frankfurt) and France. Aventis are currently carrying out phase II trials for flavopiridol in cancer and are hoping for licensing some time in 2003.
Flavopiridol does not act directly on HIV but on the HIV-infected cell. It inhibits the process of cellular transcription by interfering with the action of the protein kinase P-TEFb. This inhibition prevents the genetic material of HIV, incorporated into the nucleus of the cell, from making copies of itself as the basis of new virions. Although flavopiridol inhibits cellular transcription in most cells HIV transcription appears to be particularly sensitive allowing selective inhibition. Inhibitory concentrations determined to be effective against HIV would also allow dosing of flavopiridol lower than that currently being used in cancer chemotherapy where diarrhoea and proinflammatory syndrome affect tolerability. Flavopiridol is the most potent inhibitor of P-TEFb discovered to date in addition to being the only compound so advanced in clinical trials.
Cellular processes are an attractive target for anti-HIV drugs such as flavopiridol. Viral resistance to drugs which target HIV directly can occur rapidly due to selection of viral strains with genotypic resistance. Cellular processes are not, however, susceptible to mutation and resistance. It is therefore unlikely that viral resistance to flavopiridol would occur. Other drugs targeting cellular processes currently being used for HIV therapy include hydroxyurea and mycophenalate mofetil.
Lead investigator Prof. David Price commented that ‘since P-TEFb is a key factor in HIV-1 infection and flavopiridol blocks HIV-1 propagation in culture, we believe that this substance should be tested as a potential anti-AIDS drug’.
Rapid testing in HIV-infected subjects should be investigated and support from the activist community offered to a company with little experience in HIV therapeutics. There may be potential for salvage in those with multidrug resistant HIV with this compound.
Chao S, Koh F, Marion JE et al. Flavopiridol inhibits P-TEFb and blocks HIV-1 replication. J Biol Chem Online. July 21, 2000, 2000.