Potential class of HIV-1 integrase inhibitors

Cameron Garty is currently completing an MPhil in natural product drug discovery and medicinal chemistry in Dr Shah’s research group.

To date, seventy-eight million people in the world, have become infected with HIV and over thirty-five million deaths have resulted from HIV/AIDs and related diseases. Currently, there are between thirty-six million people living with HIV, of which two million are under the age of fifteen. The number of people with HIV receiving treatment in resource-poor countries has dramatically increased over the past decade. However, variations of HIV that develop with current medicines have led to drug-resistant strains; the search for successful therapies has not been more imperative. Understanding the function of the CD4 cells has made it possible for scientists to design antiretroviral drugs that inhibit the production of HIV by halting the process at the different stages of the life cycle. These include entry inhibitors, fusion inhibitors, reverse transcriptase inhibitors; nucleotide inhibitors, non-nucleotide inhibitors, integrase inhibitors and protease inhibitors. Currently, treatment does not cure HIV. The antiretroviral drug (ARV) therapy struggles with the issues of patient obedience, side effects, the huge cost and evolving drug resistances. More drugs against HIV targets are critical in preventing the HIV epidemic and the long term efficacy of ART. Lithospermic acid, isolated from red sage (Salvia miltiorrhiza), has been shown to inhibit HIV-1 integrase with a reported IC50 value of 0.48 M (Abd-Elazem et al., 2002). Further studies have shown it to strongly suppress HIV-1 infection in model organisms (H9 cells) with a reported IC50 value of 2 μM (Abd-Elazem et al., 2002). Currently, lithospermic acid is undergoing clinical trials as an anti-HIV drug. The overall aim of the project is to identify novel clinically active anti-HIV drugs. The objectives of the study are to synthesise a portfolio of compounds structurally similar to lithospermic acid and test against HIV-1 integrase.