Discovery of Aryl Naphthalide Lignans as Potential Anti-HIV Inhibitors from the Medicinal Plant Justicia gendarussa

Although a number of treatments are available for HIV infected patients, there is no cure for AIDS nor is there an effective vaccine to prevent HIV infection, and the efficacy of the current drugs is diminishing due to drug resistance and side effects. Thus, development of new therapeutic drugs, either in the form of a single molecule or as an herbal formula, against HIV is urgently needed. In a search for new anti-HIV active leads from over several thousands of plant extracts, we have identified a potent active lead. The active plant is Justicia gendarussa (Acanthaceae), a medicinal plant that has been used for the treatment of injury, arthritis and rheumatism in Asia including China. Our bioassay-guided fractionation of the plant extract led to the isolation of an anti- HIV compound, gendarussin A. The compound is identified as a new aryl naphthalide lignan (ANL) glycoside. It displayed potent activity against a broad spectrum of HIV strains with IC50 values in the range of 15-21 nM (AZT, IC50 77-95 nM). It is uncommon that a small-molecule natural compound isolated from a plant displayed highly potent anti-HIV activity comparable to that of the clinically used drug AZT. More study is thus needed to address the antiviral mode of action of this compound. Our study further determined ANL glycosides as major components in the active fractions of the plant extract, suggesting ANL glycosides as a new class of anti-HIV active natural products. Additionally, we observed that some of the active fractions demonstrated higher anti-HIV activity than that of gendarussin A, suggesting that other active compounds with potentially higher anti-HIV activity remain to be isolated. Therefore, more in-depth chemical and biological studies are needed to determine the therapeutic potentials of the ANL glycoside compounds. The current project is our continuing efforts to discover novel and potent anti-HIV active agents in order to develop new chemical entity drugs amenable to the treatment of HIV/AIDS disease. To achieve this goal, the following objectives and tasks are proposed: 1) to elucidate the anti-HIV mechanism of action of gendarussin A, 2) to isolate and identify additional novel ANL active compounds with anti-HIV activity from J. gendarussa; 3) to perform biological evaluation of the newly isolated ANL compounds. We expect to provide sufficient evidences for further development of ANL glycosides as anti-HIV candidates with strong therapeutic efficacy upon completion of the proposed studies.