Antiviral Activity of Nordihydroguaiaretic Acid and Its Derivative Tetra- O -Methyl Nordihydroguaiaretic Acid against West Nile Virus and Zika Virus

Abstract

Flaviviruses are positive-strand RNA viruses distributed all over the world that infect millions of people every year and for which no specific antiviral agents have been approved. These viruses include the mosquito-borne West Nile virus (WNV), which is responsible for outbreaks of meningitis and encephalitis. Considering that nordihydroguaiaretic acid (NDGA) has been previously shown to inhibit the multiplication of the related dengue virus and hepatitis C virus, we have evaluated the effect of NDGA, and its methylated derivative tetra-O-methyl nordihydroguaiaretic acid (M 4 N), on the infection of WNV. Both compounds inhibited the infection of WNV, likely by impairing viral replication. Since flavivirus multiplication is highly dependent on host cell lipid metabolism, the antiviral effect of NDGA has been previously related to its ability to disturb the lipid metabolism, probably by interfering with the sterol regulatory element-binding proteins (SREBP) pathway. Remarkably, we observed that other structurally unrelated inhibitors of the SREBP pathway, such as PF-429242 and fatostatin, also reduced WNV multiplication, supporting that the SREBP pathway may constitute a druggable target suitable for antiviral intervention against flavivirus infection. Moreover, treatment with NDGA, M 4 N, PF-429242, and fatostatin also inhibited the multiplication of the mosquito-borne flavivirus Zika virus (ZIKV), which has been recently associated with birth defects (microcephaly) and neurological disorders. Our results point to SREBP inhibitors, such as NDGA and M 4 N, as potential candidates for further antiviral development against medically relevant flaviviruses.

The A–Z of Zika drug discovery

“…Nordihydroguaiaretic acid (NDGA) and its derivative tetra-Omethyl nordihydroguaiaretic acid (M 4 N) were tested against ZIKV and showed inhibition in the low micromolar range (IC 50 values of 9.1 and 5.7 mM, respectively) [128]. They are polyphenols, whose mechanism of action is not fully elucidated (and could involve promiscuous inhibition; see the aforementioned section on PAINS in the NS2B-NS3 protease section), but NDGA has been shown to affect HCV replication through the reduction of the amount of lipid droplets, thought to be mediated by the sterol regulatory element-binding protein (SREBP) pathway [129].…”

Extracts and phenolic compounds from Zuccagnia punctata as fungicide seed protectants for corn

“…The highest inhibitory activity was observed for both DC (MIC E1/E2 = 50/50 μg dry matter mL −1 , F. verticillioides , F. graminearum sensu stricto and F. subglutinans ; MIC E1/E2 = 25/25 μg dry matter mL −1 , F. proliferatum and F. meridionale ) and Vendaval thi‐carb fv (MIC E1/E2 = 100/100 μg dry matter mL −1 on all the Fusarium species, except for F. subglutinans ). The lignan NDGA was also assayed as reference of antifungal effect because it is the major antifungal principle found in the alcoholic extract of the creosote bush ( Larrea tridentata ) which is currently used as a botanical fungicide on vegetable crops (Vogt et al, ; Merino‐Ramos et al, ). NDGA showed the same antifungal activity or 2‐fold less inhibitory activity than DC and was 8–16‐ and 4–8‐fold more active than TZP and HF, respectively.…”

Lignans and Their Derivatives from Plants as Antivirals

“…NDGA has been identified to inhibit the replication of the related dengue virus (DENV); MOA showed that it inhibits DENV infection by targeting genome replication and viral assembly [22]. Moreover, NDGA showed the effect against hepatitis C virus (HCV), West Nile Virus (WNV), and Zika Virus (ZIKV) in vitro [23,24]. For influenza A viruses (IAV), NDGA can suppress the replication of IAV and the induction of cytokines, trypsin, and MMP-9, with improved animal survival [25].…”

“…It is a methylated derivative of NDGA and was also initially founded in the resin of the creosote bush [26]. As the derivative of NDGA, it was tested the antiviral effects against WNV and ZIKV simultaneously with NDGA; the results showed both compounds inhibited the infection of WNV and ZIKA, with good and similar IC 50 values, and MOA was likely by impairing viral replication [24]. Meanwhile, Pollara showed that TMP inhibits poxvirus growth in vitro by preventing the efficient spread of virus particles from cell to cell [27].…”