Tomatidine, a natural steroidal alkaloid shows antiviral activity towards chikungunya virus in vitro

Berit Troost,Denise van de Pol,Jolanda M. Smit,Izabela A. Rodenhuis-Zybert,Mayra Diosa-Toro,Lianne M. Mulder

doi:10.1038/s41598-020-63397-7

Berit Troost, Denise van de Pol + Show 4 more

Open Access

https://doi.org/10.1038/s41598-020-63397-7

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Abstract

In recent decades, chikungunya virus (CHIKV) has re-emerged, leading to outbreaks of chikungunya fever in Africa, Asia and Central and South America. The disease is characterized by a rapid onset febrile illness with (poly)arthralgia, myalgia, rashes, headaches and nausea. In 30 to 40% of the cases, CHIKV infection causes persistent (poly)arthralgia, lasting for months or even years after initial infection. Despite the drastic re-emergence and clinical impact there is no vaccine nor antiviral compound available to prevent or control CHIKV infection. Here, we evaluated the antiviral potential of tomatidine towards CHIKV infection. We demonstrate that tomatidine potently inhibits virus particle production of multiple CHIKV strains. Time-of -addition experiments in Huh7 cells revealed that tomatidine acts at a post-entry step of the virus replication cycle. Furthermore, a marked decrease in the number of CHIKV-infected cells was seen, suggesting that tomatidine predominantly acts early in infection yet after virus attachment and cell entry. Antiviral activity was still detected at 24 hours post-infection, indicating that tomatidine controls multiple rounds of CHIKV replication. Solasodine and sarsasapogenin, two structural derivatives of tomatidine, also showed strong albeit less potent antiviral activity towards CHIKV. In conclusion, this study identifies tomatidine as a novel compound to combat CHIKV infection in vitro.

Highlights

In recent decades, chikungunya virus (CHIKV) has re-emerged, leading to outbreaks of chikungunya fever in Africa, Asia and Central and South America
Vero-WHO cells were incubated with 10 μM tomatidine or the equivalent volume of EtOH and infected with CHIKV-LR at multiplicity of infection (MOI) 0.5
In order to further validate the antiviral effect of tomatidine towards CHIKV, we evaluated its antiviral potential in two other human cell lines relevant during natural CHIKV infection, namely, skin fibroblast HFF-1 cells and bone osteosarcoma U2OS cells[28,29,30]

Summary

Introduction

Chikungunya virus (CHIKV) has re-emerged, leading to outbreaks of chikungunya fever in Africa, Asia and Central and South America. Despite the drastic re-emergence and clinical impact there is no vaccine nor antiviral compound available to prevent or control CHIKV infection. CHIKV re-emerged and caused various large outbreaks in Africa, Asia and Central and South America[2,3]. Among those was an explosive epidemic on the Indian Ocean island of La Reunion, where over 266.000 people were affected[4]. We recently identified tomatidine as a novel antiviral compound towards two re-emerging mosquito-borne flaviviruses: dengue virus (DENV) and zika virus (ZIKV)[21]. No antiviral activity was observed for West Nile virus (WNV), a closely related mosquito-borne flavivirus

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