To Develop Arylnaphthalene Lignans as Potent Inhibitors Against HIV through Chemical Synthesis

AIDS has killed more than 35 million people since its first report in 1981. The number of HIV infected cases in China have been skyrocketing from 2008 to 2016. The current treatment for HIV infected patients has no cure for AIDS, and HIV often develops resistance to the antiviral drugs. To discover and further develop novel anti-HIV agents is very much needed. In a search for new anti-HIV active lead compounds from plant extracts, we have identified several anti-HIV arylnaphthalene lignan (ANL) glycosides from a medicinal plant in the genus Justicia (Acanthaceae). The ANL compounds displayed potent activity against a broad spectrum of HIV clinical strains with IC50 values in the range of 14-37 nM (the clinically used drug AZT: IC 50 77-95 nM). We further synthesized, de novo, one (patentiflorin A: F85) of the ANL compounds. The synthesized F85 was determined to have therapeutic index of more than 1,000. Importantly, the compound displayed potent inhibitory activity against drug-resistant HIV-1 isolates of both the nucleotide analogue (AZT) and the non-nucleotide analogue (nevaripine), thus establishing these ANL compounds as a class of potent anti-HIV lead compounds. Our preliminary data indicated that F85 is not an inhibitor of reverse transcriptase, but its antiviral mechanism is still unknown. Hence, in-depth chemical and biological studies are needed to elucidate the antiviral mechanism and determine the therapeutic potentials of these compounds. The long-term goal of this proposed study is to advance the anti-HIV ANL compounds as potential candidates amenable for the treatment of HIV/AIDS. To achieve this goal, we propose to:
1) chemically synthesize ANL analogues with diversified functional groups substituted at C-7, which will include nucleotide-containing ANLs and ANL glycosides;
2) determine the anti-HIV mechanism of action through identification of the antiviral target(s) of ANL compounds. Molecular docking analysis and binding assays will serve as efficient tools to identify the antiviral target(s) of ANL compounds;
3) assess the anti-HIV activity of ANL compounds using an in vitro evaluation system; followed by confirmation of the anti-HIV activity of the active compounds in a broad spectrum of clinically used HIV-1 strains, including resistant strains; and to investigate the toxicity and metabolic effects of the confirmed active ANL analogues in animal models.

We expect to provide sufficient evidences for the further development of ANL compounds as potential anti-HIV drug candidates with strong therapeutic efficacy upon completion of the proposed studies.