Anti-dengue activity of a cellular lipid uptake inhibitor, lipofermata

Abstract

There is still no effective antiviral drug for Dengue virus (DENV). Fatty acid (FA) was previously shown to be essential for DENV replication. The availability of intracellular FA depends on both intracellular synthesis and uptake from extracellular sources. While inhibition of FA synthesis has been shown to hinder DENV replication, less is known about inhibition of cellular FA uptake. Fatty acid transporter isoform 2 (FATP2) is known to be highly expressed in hepatocyte, the major target cell of DENV. An immortalized hepatocyte-like cell line (imHC) was used to determine anti-DENV2 activity and FA uptake inhibitory function of Lipofermata (FATP2 inhibitor). FATP2 protein expression level was measured in DENV2-infected cell by western blotting. Finally, Synergistic effect of combination of Lipofermata and Orlistat (FA synthesis inhibitor) was evaluated. Lipofermata could inhibit DENV1 and DENV2 with a 50% inhibitory concentration (IC<inf>50</inf>) of 1.75 and 1.74 µM, respectively with a similar selectivity index of 3.4. FATP2 expression level was significantly upregulated by DENV2 infection. A combination of Lipofermata with Orlistat, a FA synthesis inhibitor, showed additive or synergistic inhibitory effects on DENV2 in drug synergy prediction models. Cellular FA uptake is therefore a promising target for new anti-DENV drug development.