Theaflavin 3,3'-digallate (TF-3) is a potent Zika virus (ZIKV) protease inhibitor with an IC50 of 2.3 μM. Theaflavin 3,3'-digallat directly binds to ZIKVpro (Kd=8.86 µM) and inhibits ZIKV replication. Theaflavin 3,3'-digallat inhibits the activity of gp41 and NS2B-3 protease and has antiviral activity against HSV and HIV-1. Theaflavin 3,3'-digallate (TF-3; 6.25, 12.5, 25 μM; 24 hours) markedly reduces viral RNA copy numbers and NS3, U87 MG protein expression in a dose-dependent manner. Theaflavin 3,3'-digallate inhibits dose-dependently ZIKV replication in Vero E6 cells (EC50=7.65 μM). Theaflavin 3,3'-digallate has minor cytotoxicity up to 40 μM in Vero E6 cells. Theaflavin 3,3'-digallate can inhibit the post-entry events of the ZIKV replication cycle from gene transcription and translation levels. Theaflavin 3,3'-digallate is generally regarded as the effective component for the inhibitory effects against carcinogenesis without adverse side effects by affecting multiple signal transduction pathways, such as upregulating p53 and p21, inhibiting phosphorylation of the cell survival protein Akt and MAPK pathway, downregulation of NF-κB, shifting the ratio between pro-/antiapoptotic proteins. Theaflavin 3,3'-digallate causes a rapid and sustained decrease in phospho-ERK1/2 and -MEK1/2 protein expression. Theaflavin 3,3'-digallate inhibits HCT116 cell growth with an IC50 of 17.26 μM[1]. TF3 may have the potential to treat osteoporosis and bone diseases related to excessive osteoclastogenesis via inhibiting the intracellular ROS (reactive oxygen species) level[2]. TF3 enhanced the phosphorylation of Chk2 (checkpoint kinase 2) to modulate the ratio of pro/anti-apoptotic Bcl-2 family proteins to initiate intrinsic apoptosis in a p53-independent manner and increased the expression of death receptors to activate extrinsic apoptosis in OVCAR-3 human ovarian carcinoma cells. In addition, TF3 up-regulated the expression of p27 to induce G0/G1 cell cycle arrest in OVCAR-3 cells[3].
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