Abstract

BackgroundThe worldwide epidemics of diseases as dengue and Zika have triggered an intense effort to repurpose drugs and search for novel antivirals to treat patients as no approved drugs for these diseases are currently available. Our aim was to screen plant-derived extracts to identify and isolate compounds with antiviral properties against dengue virus (DENV) and Zika virus (ZIKV).MethodsSeven thousand plant extracts were screened in vitro for their antiviral properties against DENV-2 and ZIKV by their viral cytopathic effect reduction followed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, previously validated for this purpose. Selected extracts were submitted to bioactivity-guided fractionation using high- and ultrahigh-pressure liquid chromatography. In parallel, high-resolution mass spectrometric data (MSn) were collected from each fraction, allowing compounds into the active fractions to be tracked in subsequent fractionation procedures. The virucidal activity of extracts and compounds was assessed by using the plaque reduction assay. EC50 and CC50 were determined by dose response experiments, and the ratio (EC50/CC50) was used as a selectivity index (SI) to measure the antiviral vs. cytotoxic activity. Purified compounds were used in nuclear magnetic resonance spectroscopy to identify their chemical structures. Two compounds were associated in different proportions and submitted to bioassays against both viruses to investigate possible synergy. In silico prediction of the pharmacokinetic and toxicity (ADMET) properties of the antiviral compounds were calculated using the pkCSM platform.ResultsWe detected antiviral activity against DENV-2 and ZIKV in 21 extracts obtained from 15 plant species. Hippeastrum (Amaryllidaceae) was the most represented genus, affording seven active extracts. Bioactivity-guided fractionation of several extracts led to the purification of lycorine, pretazettine, narciclasine, and narciclasine-4-O-β-D-xylopyranoside (NXP). Another 16 compounds were identified in active fractions. Association of lycorine and pretazettine did not improve their antiviral activity against DENV-2 and neither to ZIKV. ADMET prediction suggested that these four compounds may have a good metabolism and no mutagenic toxicity. Predicted oral absorption, distribution, and excretion parameters of lycorine and pretazettine indicate them as candidates to be tested in animal models.ConclusionsOur results showed that plant extracts, especially those from the Hippeastrum genus, can be a valuable source of antiviral compounds against ZIKV and DENV-2. The majority of compounds identified have never been previously described for their activity against ZIKV and other viruses.

Highlights

  • Zika virus (ZIKV) and Dengue virus (DENV), members of the Flaviviridae family, are arboviruses of great importance in human Public Health worldwide

  • Our results showed that plant extracts, especially those from the Hippeastrum genus, can be a valu‐ able source of antiviral compounds against ZIKV and dengue virus (DENV)-2

  • The MTT method is a reliable tool for antiviral high‐throughput screening (HTS) against DENV and ZIKV The results of the validation of the MTT method for antiviral High Throughput Screening (HTS) against ZIKV in Vero cells and Dengue virus serotype 2 (DENV-2) in BHK21 cells are shown in Additional file 1: Figs

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Summary

Introduction

Zika virus (ZIKV) and Dengue virus (DENV), members of the Flaviviridae family, are arboviruses of great importance in human Public Health worldwide. Different approaches and methodologies have been used for drug repurposing to find antivirals against ZIKV and DENV, such as testing specific compounds with known antiviral activity in other virus models and screening of libraries composed of hundreds of bioactive molecules, many of them already approved for human use. These molecules target viral and cellular components, including nucleosides analogues, nucleoside synthesis inhibitors, drugs targeting viral enzymes, anticancer and anti-inflammatory molecules, antibiotics, antiparasitics, among others [11, 14]. Our aim was to screen plant-derived extracts to identify and isolate compounds with antiviral properties against dengue virus (DENV) and Zika virus (ZIKV)

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