The long-term goal of this research is to develop drugs that are safe and effective against drug-resistant human immunodeficiency virus (HIV) infection. Several challenges confront current anti-HIV chemotherapy. The frequency of drug resistant and multi-drug resistant HIV-1 is increasing. Toxicities often require the discontinuation of anti-HIV therapy in some patients. Physicians are left with few anti-HIV drugs to prescribe once drug resistance and/or toxicity develop in patients. Thus, drugs with novel mechanisms of action that are potent, and with reduced cytotoxicity are needed. INK-11 is an anti-HIV-1 phospholipid with a novel mechanism of action distinct from existing anti-HIV compounds. Preliminary studies of INK-11 indicate that it is a potent, highly active compound against HIV-1 in vitro. This compound markedly inhibits matched pairs of AZT-sensitive and AZT resistant human clinical isolates of HIV-1. The goal of this Phase I SBIR grant is to conduct small scale-up synthesis of INK-11 that will permit the completion of key, proof of principal, preclinical studies.
The specific aims of this project include the determination of the activity of INK-11 against wild-type HIV-1 and the cytotoxicity of INK-11 in a variety of cell lines. Its activity against cells chronically infected with HIV-1 and the effect of multiplicity of infection on its activity will be examined. Finally, the activity of INK-11 against a panel of resistant HIV-1 variants will be evaluated. INK-11 will be synthesized using a method developed by our research team. The synthesized compound will be used to complete the in vitro studies noted above and will also aid in the conduct of future in vivo studies. These studies may identify INK-11 as a candidate for future clinical trials in HIV.
