The primary goal of this study is to determine the mechanism of action (MOA) of two classes of potent anti-HIV agents, triterpene derivatives (TD) and coumarin derivatives such as camphanoyl khellactone (DCK). Both classes of anti-HIV agents inhibit HIV at nonomolar concentrations. More importantly, the modes of action of these anti-HIV agents appear to be novel. For example, DCK does not inhibit the known anti-HIV targets such as protease and reverse transcriptase. Similar to that of DCK, the MOA of TD is different from those of the drugs currently used for anti- HIV therapy. To study the MOA of these compounds, specific experiments for each class of compounds will be designed based on the information obtained from our preliminary studies. For instance, the MOA studies of DCK will e focused on the genetic analysis of drug resistant mutants since DCK has eluded characterization in most of the known targets. On the other hand, our preliminary results offer significant clues for us to study the MOA of certain TD at specific site of action. Our studies indicate that there are two types of TD, E-TD and N-TD, each with a different site of action. The E-TD target virus entry. Therefore, the MOA study will focus on the interaction between the drug and HIV-1 envelope, The target(s) of the N-TD is unknown. To study the MOA of N-TD, systematic approaches will be used to identify the drug sensitive phase of the viral life cycle. Their activity against known viral agents will be evaluated depending on which stage of the virus life cycle is sensitive to N-TD. If N-TD pharmacologically behave similarly to that of DCK, i.e. no activity against most of the known targets, the MOA studies will focus on drug resistant viruses. The use of highly active anti-retroviral therapy (HAART) has been shown to be very effective in controlling HIV-1 plasma viremia. However, persistent HIV-1 replication was demonstrated in patients receiving HAART. Potent anti-HIV compounds with novel modes of action not only could add to the repertoire HAART but might also impact the viral reservoirs that evade current drug regimens. Our hypothesis is that DCK and TD are potent anti-HIV-1 compounds with novel modes of action. Identification of the targets of these compounds will facilitate future drug development for an optimal anti-HIV therapy. In addition, these compounds could be very useful in studying the biology of the HIV life cycle such as the viral entry process.
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