Antiviral Properties of the Natural Polyphenols Delphinidin and Epigallocatechin Gallate against the Flaviviruses West Nile Virus, Zika Virus, and Dengue Virus

Abstract

The Flavivirus genus contains important pathogens, such as West Nile virus (WNV), Zika virus (ZIKV), and Dengue virus (DENV), which are enveloped plus-strand RNA viruses transmitted by mosquitoes and constitute a worrisome threat to global human and animal health. Currently no licensed drugs against them are available, being, thus, still necessary the search for effective antiviral molecules. In this line, a novel antiviral approach (economical, simple to use, and environmental friendly) is the use of natural compounds. Consequently, we have tested the antiviral potential of different polyphenols present in plants and natural products, such as wine and tea, against WNV, ZIKV, and DENV. So that, we assayed the effect of a panel of structurally related polyphenols [delphinidin (D), cyanidin (Cy), catechin (C), epicatechin (EC), epigallocatechin (EGC), and epigallocatechin gallate (EGCG)] on WNV infection, and found that D and EGCG inhibited more effectively the virus production. Further analysis with both compounds indicated that they mainly affected the attachment and entry steps of the virus life cycle. Moreover, D and EGCG showed a direct effect on WNV particles exerting a virucidal effect. We showed a similar inhibition of viral production of these compounds on WNV variants that differed on acidic pH requirements for viral fusion, indicating that their antiviral activity against WNV is produced by a virucidal effect rather than by an inhibition of pH-dependent viral fusion. Both polyphenols also reduced the infectivity of ZIKV and DENV. Therefore, D and EGCG impair the infectivity in cell culture of these three medically relevant flaviviruses.

Antiviral Mechanism of Action of Epigallocatechin-3-O-gallate and Its Fatty Acid Esters

“…However, no or minimal inhibition was observed with other flavivirus, including JEV, YFV, and ZIKV, contradicting previous reports by Carneiro [20] and Vázquz-Calvo [23]. In those reports, ZIKV particles were incubated with EGCG for 1 h before the mixture was applied to cells.…”

“…That the same year, Vázquz-Calvo et al [23] assayed the effect of a series of polyphenols on WNV-NY99 infection and found that delphinidin ( 14 ) and EGCG ( 1 ) reduced the viral titer by more than three orders of magnitude as the virus pretreated with 10 μM of each polyphenol. These compounds mainly affected the attachment and entry steps of the virus life cycle.…”

“…Regarding these biological properties, EGCG ( 1 ) has been reported to possess a broad spectrum of antiviral activities against DNA viruses such as herpes simplex virus (HSV; Herpesviridae ) [5,6,7,8,9,10,11], adenovirus ( Adenoviridae ) [10,12], human papilloma virus (HPV; Papovaviridae ) [13], and hepatitis B virus (HBV; Hepadnaviridae ) [14], and against (+)-RNA viruses such as hepatitis C virus (HCV; Flaviviridae ) [10,15,16,17,18,19], Zika virus (ZIKV; Flaviviridae ) [20,21,22,23], dengue virus (DENV; Flaviviridae ) [23,24], West Nile viruses (WNV; Flaviviridae ) [23], Chikungunya virus (CHIKV; Togaviridae ) [25], and Porcine Reproductive and Respiratory virus (PRRS; Atteriviridae ) [26], and (−)-RNA viruses such as human immunodeficiency virus (HIV; Retroviridae ) [27,28,29,30,31,32,33,34,35,36], Ebola virus (EBOV; Filoviridae ) [37] and influenza virus ( Orthomyxoviridae ) [2,10,38,39,40,41,42,43,44,45,46,47,48]. …”

Host-Directed Antivirals: a Realistic Alternative to Fight Zika Virus

“…The crystal structures of all these proteins have been already resolved and will certainly help to find new antivirals [22][23][24][25][26][27][28][29][30]. In the same way, structures from other viral proteins are also available that could help to design ZIKV therapeutic alternatives, such as those of the capsid C protein [31], which destabilization may impair ZIKV multiplication, the NS1 [32,33], an immunomodulator, or the envelope glycoprotein [34][35][36], which mediates cell binding and endosomal fusion, constitutes a major target for neutralizing antibodies, and could be also the target for virucidal compounds [37].…”

Zika Virus: What Have We Learnt Since the Start of the Recent Epidemic?

“…Even more, compounds present in many natural products that also target the viral particle, such as the polyphenols epigallocatechin gallate and delphinidin chloride, also exhibit anti-ZIKV activity, probably through a virucidal effect Vázquez-Calvo et al, 2017b).…”