Abstract
Ipecac alkaloids are secondary metabolites produced in the medicinal plant Psychotria ipecacuanha. Emetine is the main alkaloid of ipecac and one of the active compounds in syrup of Ipecac with emetic property. Here we evaluated emetine’s potential as an antiviral agent against Human Immunodeficiency Virus. We performed in vitro Reverse Transcriptase (RT) Assay and Natural Endogenous Reverse Transcriptase Activity Assay (NERT) to evaluate HIV RT inhibition. Emetine molecular docking on HIV-1 RT was also analyzed. Phenotypic assays were performed in non-lymphocytic and in Peripheral Blood Mononuclear Cells (PBMC) with HIV-1 wild-type and HIV-harboring RT-resistant mutation to Nucleoside Reverse Transcriptase Inhibitors (M184V). Our results showed that HIV-1 RT was blocked in the presence of emetine in both models: in vitro reactions with isolated HIV-1 RT and intravirion, measured by NERT. Emetine revealed a strong potential of inhibiting HIV-1 replication in both cellular models, reaching 80% of reduction in HIV-1 infection, with low cytotoxic effect. Emetine also blocked HIV-1 infection of RT M184V mutant. These results suggest that emetine is able to penetrate in intact HIV particles, and bind and block reverse transcription reaction, suggesting that it can be used as anti-HIV microbicide. Taken together, our findings provide additional pharmacological information on the potential therapeutic effects of emetine.
Highlights
Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome (AIDS), which is estimated to affect 35 million people globally, as reported in 2013 [1].Lymphocytes T CD4+ and monocyte/macrophages are the HIV-1 target cells [2].As a human retrovirus, once internalized, the HIV RNA genome is reverse-transcribed by ReverseTranscriptase (RT) enzyme to a double-stranded DNA that is further integrated into host DNA [3]
Our results demonstrated that emetine blocks HIV-1 infection in primary and established cells in non-cytotoxic levels and its effects are mediated by reverse transcription inhibition
We explored if emetine could block HIV-1 Reverse Transcriptase (RT) activity directly in cell-free virus particles
Summary
Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome (AIDS), which is estimated to affect 35 million people globally, as reported in 2013 [1]. Active antiretroviral therapy (HAART) is the currently available combination therapy for HIV-1 that targets different steps in the virus replication [11]. A previous study showed that alkaloids extracted from ipecac root were potent inhibitors of HIV. Between the alkaloids tested, emetine exhibited a low in vitro potential of inhibition of HIV-1 RT at a concentration of 400 μg·mL−1, but this study was not extended in the context of HIV. Our results demonstrated that emetine blocks HIV-1 infection in primary and established cells in non-cytotoxic levels and its effects are mediated by reverse transcription inhibition. Emetine blocks HIV-1 infection of a variant strain harboring RT-resistant mutation to NRTIs, suggesting the importance of further studies to evaluate the potential use of this compound as an anti-HIV inhibitor
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