Abstract
Andrographolide is a labdene diterpenoid with potential applications against a number of viruses, including the mosquito-transmitted dengue virus (DENV). In this study, we evaluated the anti-viral activity of three 14-aryloxy analogues (ZAD-1 to ZAD-3) of andrographolide against Zika virus (ZIKV) and DENV. Interestingly, one analogue, ZAD-1, showed better activity against both ZIKV and DENV than the parental andrographolide. A two-dimension (2D) proteomic analysis of human A549 cells treated with ZAD-1 compared to cells treated with andrographolide identified four differentially expressed proteins (heat shock 70 kDa protein 1 (HSPA1A), phosphoglycerate kinase 1 (PGK1), transketolase (TKT) and GTP-binding nuclear protein Ran (Ran)). Western blot analysis confirmed that ZAD-1 treatment downregulated expression of HSPA1A and upregulated expression of PGK1 as compared to andrographolide treatment. These results suggest that 14-aryloxy analogues of andrographolide have the potential for further development as anti-DENV and anti-ZIKV agents.
Highlights
The genus Flavivirus of the family Flaviviridae contains some 53 viral species [1], of which 27 are transmitted primarily by Culex spp. or Aedes (Ae.) spp. mosquitoes
Results showed that 25 μM andrographolide significantly increased HSPA1A expression compared with the vehicle control, while ZAD-1 treatment showed no significant difference from control (Figure 6A)
phosphoglycerate kinase 1 (PGK1) expression in 25 μM andrographolide-treated cells was significantly upregulated relative to the vehicle, and ZAD-1 treatment resulted in significantly increased expression as compared to andrographolide treatment
Summary
The genus Flavivirus of the family Flaviviridae contains some 53 viral species [1], of which 27 are transmitted primarily by Culex spp. or Aedes (Ae.) spp. mosquitoes. Members of this genus, which includes yellow fever virus (YFV), Japanese encephalitis virus (JEV), West Nile virus, dengue virus (DENV) and Zika virus (ZIKV), impose a significant public health burden in many tropical and subtropical countries around the world. Lack of universal vaccine coverage in areas of transmission, coupled with the lack of a commercial vaccine for the majority of mosquito-transmitted flaviviruses, necessitates the development of effective treatment options, but currently there is no approved drug to treat any flaviviral infection. The search for effective drugs to treat infections with these viruses is a high priority
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