Before the 2022 American Society of Hepatology Annual Meeting (AASLD2022), researchers introduced a new advance in drug discovery related to cccDNA. The study pointed out that novel furancoumarin targets cccDNA and inhibits HBVDNA replication and the expression of viral genes.
Hepatitis B drug found that the novel furancoumarin FC-20/31 has reduced preclinical cccDNA by more than 2 log
At present, the hepatitis B virus (HBV) infection therapy used targets reverse transcriptase, effectively limiting the replication of HBV, but cannot eradicate the viral DNA template in the host, that is, covalently closed circular DNA (cccDNA). There is a need to develop novel antiviral drugs for cccDNA, HBsAg release, viral gene expression, and capsid assembly.
researchers say recent preclinical studies have shown that coumarins can effectively block HBV replication. In addition, plant-derived furocomumarin has strong antiviral activity against HIV-1 and influenza viruses. In this study, the antiviral efficacy of novel coumarin and furocoumarin on HBV replication and gene expression was tested.
35 novel coumarin and furocoumarin were chemically synthesized using silver-mediated oxidative C-H/functionalized C-H (acetylene sp-hybrid carbon in coumarin/chromoprotoketone, sp3-hybrid carbon in acetoacetate ) and tested their antiviral activities in human hepatoblastoma HepG2.2.15 (with stable integrated HBV genome) and HepG2-NTCP cells (HBV infection overexpressing HBV receptors).
HBV and cccDNA levels and viral RNA and protein expression were detected by qPCR, RT-qPCR and ELISA, respectively. The in vitro cytotoxic effect at a concentration of 1-500μM was detected by the MTT method.
study results show that among the 35 compounds tested, furocoumarin-20 (FC-20) and furocoumarin-31 (FC-31) can effectively inhibit the replication of hepatitis B virus in HepG2.2.15 and HepG2-NTCP cells. In the presence of FC-31, the levels of HBVDNA, progenomic (pg) RNA, HBsAg and HBeAg significantly decreased by 2.7, 3.8, 17.7 and 16.3 times, respectively, while in the presence of FC-20, the levels of HBVDNA, progenomic (pg) RNA, HBsAg and HBeAg significantly decreased by 2.1, 3.2, 11.5 and 14.8 times, respectively. Compared with
and FC-20 (IC50 =42.3 ± 0.33 μM), FC-31 (IC50 =31.3 ± 0.23 μM) had more obvious inhibition of HBVDNA (p 0.005), pgRNA (p 0.005), viral proteins HBeAg (p 0.001), HBsAg (p 0.001) and HBx levels.
From AASLD2022
FC-20 and FC-31 (at 50mM) both showed a decrease in cccDNA copy number by more than 2 logs (Figure 1A), and a decrease in HBx levels (Figure 1B). Importantly, FC-20 and FC-31 were not toxic to cells even at a concentration of 500 μM (Fig. 1C).
Research conclusion: Furancoumarin FC-20 and FC-31 can effectively inhibit the replication of hepatitis B virus and the expression of viral genes. The therapeutic potential of these compounds should be further evaluated.
