Abstract
The introduction of highly active antiretroviral therapy has led to a significant reduction in the morbidity and mortality of acquired immunodeficiency syndrome patients. However, the emergence of drug resistance has resulted in the failure of treatments in large numbers of patients and thus necessitates the development of new classes of anti-HIV drugs. In this study, more than 200 plant-derived small-molecule compounds were evaluated in a cell-based HIV-1 antiviral screen, resulting in the identification of a novel HIV-1 inhibitor (fangchinoline). Fangchinoline, a bisbenzylisoquinoline alkaloid isolated from Radix Stephaniae tetrandrae, exhibited antiviral activity against HIV-1 laboratory strains NL4-3, LAI and BaL in MT-4 and PM1 cells with a 50% effective concentration ranging from 0.8 to 1.7 µM. Mechanism-of-action studies showed that fangchinoline did not exhibit measurable antiviral activity in TZM-b1 cells but did inhibit the production of infectious virions in HIV-1 cDNA transfected 293T cells, which suggests that the compound targets a late event in infection cycle. Furthermore, the antiviral effect of fangchinoline seems to be HIV-1 enve1ope-dependent, as the production of infectious HIV-1 particles packaged with a heterologous envelope, the vesicular stomatitis virus G glycoprotein, was unaffected by fangchinoline. Western blot analysis of HIV envelope proteins expressed in transfected 293T cells and in isolated virions showed that fangchinoline inhibited HIV-1 gp160 processing, resulting in reduced envelope glycoprotein incorporation into nascent virions. Collectively, our results demonstrate that fangchinoline inhibits HIV-1 replication by interfering with gp160 proteolytic processing. Fangchinoline may serve as a starting point for developing a new HIV-1 therapeutic approach.
Highlights
The global epidemic of acquired immunodeficiency syndrome (AIDS) remains one of the most pressing public health emergencies
We screened more than 200 compounds, which were isolated from traditional Chinese medicinal herbs, using a full viral replication cycle assay resulting in the identification of fangchinoline as a novel anti-HIV-1 agent (Fig. 1)
Our unpublished data showed that fangchinoline did not show an inhibitory effect on virus-induced cytopathic effect (CPE) in influenza virusinfected MDCK cells or on HBV HBeAg or HBsAg expression in HepG2.117 cells, which indicates that the antiviral activity of fangchinoline may be specific to HIV-1
Summary
The global epidemic of acquired immunodeficiency syndrome (AIDS) remains one of the most pressing public health emergencies. Since the emergence of HIV, intensive studies have been undertaken to understand the disease and find effective therapies. Highly active antiretroviral therapy (HAART) is considered to be the standard therapy formula and has been proven to be successful in controlling viral replication and disease progression. Prolonged treatment with combination regimens can be difficult to sustain because of problems with adherence and toxic effects [1,2]. In a significant portion of treatment-experienced patients, therapeutic options are limited due to the emergence of drug resistance [3]. Cross-resistance between drugs within a class frequently occurs [4]. The discovery and development of drugs targeting alternative mechanisms in the HIV-1 replication cycle should be the most effective strategy to overcome drug resistance
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