Abstract
Zika virus (ZIKV) is a mosquito-transmitted Flavivirus, originally identified in Uganda in 1947 and recently associated with a large outbreak in South America. Despite extensive efforts there are currently no approved antiviral compounds for treatment of ZIKV infection. Here we describe the antiviral activity of diarylamines derived from anthranilic acid (FAMs) against ZIKV. A synthetic FAM (E3) demonstrated anti-ZIKV potential by reducing viral replication up to 86%. We analyzed the possible mechanisms of action of FAM E3 by evaluating the intercalation of this compound into the viral dsRNA and its interaction with the RNA polymerase of bacteriophage SP6. However, FAM E3 did not act by these mechanisms. In silico results predicted that FAM E3 might bind to the ZIKV NS3 helicase suggesting that this protein could be one possible target of this compound. To test this, the thermal stability and the ATPase activity of the ZIKV NS3 helicase domain (NS3Hel) were investigated in vitro and we demonstrated that FAM E3 could indeed bind to and stabilize NS3Hel.
Highlights
Zika virus (ZIKV) is a mosquito - transmitted virus first isolated in 1947 from a Rhesus monkey in the Zika forest, Uganda[1]
Our data showed that FAM E3 was able to inhibit >99% of virus replication, while the minimum cell viability remained above 60% (Fig. 1C)
In this study we evaluated the ability of synthetic diarylamines derived from anthranilic acid (FAMs), designed based on their natural scaffolds, to inhibit ZIKV infection
Summary
Zika virus (ZIKV) is a mosquito - transmitted virus first isolated in 1947 from a Rhesus monkey in the Zika forest, Uganda[1]. There is an urgent need for research to develop effective antivirals In this context, the therapeutic properties of natural compounds have been historically described for the treatment of several viral diseases, such as hepatitis C virus (HCV)[19,20], human immunodeficiency virus (HIV-1)[21], CHIKV22, DENV and West Nile virus (WNV)[23]. Natural and synthetic acids have attracted attention due to their potent antiviral properties. This is exemplified by glycyrrhizic acid which prevents the release of HCV infectious particles[29] and inhibits hepatitis A virus (HAV) penetration into the host cell[30], and 3,5-dicaffeoylquinic acid, 1-methoxyoxalyl-3,5-dicaffeoylquinic acid, and L-chicoric acid that were described to prevent HIV-1 viral replication[31]. Nordihydroguaiaretic acid (NDGA) and its derivative tetra-o-methyl nordihydroguaiaretic acid were demonstrated to block DENV, HCV32, WNV and ZIKV33 replication
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