Using Naturally Derived Compounds to Combat HIV: A Case for Complementary and Alternative Medicinal Modalities

Abstract

Anti‐retroviral therapies for AIDS have typically targeted HIV proteins integrase, protease, and reverse transcriptase. Transactivator of transcription (Tat), an early HIV protein that increases the efficiency of proviral transcription, and replication, is now being looked at as a possible new target for anti‐HIV therapies. We have previously shown that electrophilic prostaglandin, 15d‐PGJ2, is capable of modifying the Cys rich region in Tat irreversibly such that it loses its transactivating property. In an effort to identify more such molecules, which can inhibit Tat, we have explored a selected few naturally derived compounds with electrophilic carbon centers. Of the several compounds tested, celastrol, a triterpene extracted from Tripterygium wilfordii, inhibited Tat‐dependent HIV transcription and replication at low concentrations, and that this inhibition was independent of the NF‐kappa B pathway. Using a biotinylated derivative of celastrol, we show that the Cys‐thiols in Tat are targeted in a covalent Michael addition reaction. Furthermore, circular dichroism spectroscopy was used to demonstrate changes in the secondary structure of Tat upon interaction with celastrol. Thus, a structural perturbation of Tat could likely impact the processivity of RNA polymerase II, leading to the inhibition of transcription. These data suggest that redox‐modulating natural compounds such as celastrol have the potential to be developed as anti‐retroviral therapeutics for HIVAIDS.