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Open Access 01-12-2022 | Dengue Virus | Research

Searching for plant-derived antivirals against dengue virus and Zika virus

Authors: Emerson de Castro Barbosa, Tânia Maria Almeida Alves, Markus Kohlhoff, Soraya Torres Gaze Jangola, Douglas Eduardo Valente Pires, Anna Carolina Cançado Figueiredo, Érica Alessandra Rocha Alves, Carlos Eduardo Calzavara-Silva, Marcos Sobral, Erna Geessien Kroon, Luiz Henrique Rosa, Carlos Leomar Zani, Jaquelline Germano de Oliveira

Published in: Virology Journal | Issue 1/2022

Abstract

Background

The 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).

Methods

Seven 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.

Results

We 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.

Conclusions

Our 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.

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Title: Searching for plant-derived antivirals against dengue virus and Zika virus
Authors: Emerson de Castro Barbosa
Tânia Maria Almeida Alves
Markus Kohlhoff
Soraya Torres Gaze Jangola
Douglas Eduardo Valente Pires
Anna Carolina Cançado Figueiredo
Érica Alessandra Rocha Alves
Carlos Eduardo Calzavara-Silva
Marcos Sobral
Erna Geessien Kroon
Luiz Henrique Rosa
Carlos Leomar Zani
Jaquelline Germano de Oliveira
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Dengue Virus
Zika Virus
Alkaloids
Alkaloids
Published in: Virology Journal / Issue 1/2022
Electronic ISSN: 1743-422X
DOI: https://doi.org/10.1186/s12985-022-01751-z

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