These authors contributed equally to this work.
Therapeutic potential of furin inhibitors for the chronic infection of hepatitis B virus
Article first published online: 25 APR 2013
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Volume 33, Issue 8, pages 1230–1238, September 2013
How to Cite
Liver Int. 2013: 33: 1230–1238
- Issue published online: 11 AUG 2013
- Article first published online: 25 APR 2013
- Accepted manuscript online: 4 APR 2013 02:07AM EST
- Manuscript Accepted: 1 APR 2013
- Manuscript Received: 22 NOV 2012
- National Nature Scientific Foundation. Grant Numbers: 30872224, 81071366
- Scientific and Technological Hall of Guangdong Province. Grant Numbers: 2009B030801084, 10251008901000018
- chronic hepatitis B;
- hepatitis B e antigen;
- Hepatitis B virus;
- proprotein convertase;
- protease inhibitor
Background & Aims
Hepatitis B e antigen (HBeAg) is essential for the development of chronic hepatitis B virus (HBV) infection. Furin, a proprotein convertase, plays a key role in processing of HBeAg precursor into maturated HBeAg. For these reasons, the therapeutic potential of furin inhibition for chronic HBV infection was studied.
The effects of furin inhibitor I (decanoyl-RVKR-chloromethylketone, CMK) and furin inhibitor II (hexa-D-arginine, D6R) on HBeAg secretion, the destination of unprocessed precursor and cellular secretory functions were comparatively investigated.
CMK and D6R significantly decreased the supernatant level of HBeAg and increased the intracellular level of HBeAg precursor in HepG2.2.15 cells in vitro. The accumulated HBeAg precursor was not found to be retro-transported into the cytosol to inhibit HBV replication as expected, but was found to be expressed on the cell surface, where it may be more convenient to mediate host immune responses. Furthermore, these inhibitors at effective concentrations were not found to interfere with the maturations of albumin and prothrombin. Compared with CMK, D6R was suboptimal in effectiveness; however, D6R neither enhanced HBV replication through the accumulation of cytosolic HBcAg nor did it cause severe cell damage in an elongated safety analyses.
Furin inhibitors CMK and D6R reduce HBeAg secretion and increase cell surface expression of the HBeAg precursor in HepG2.2.15 cells. Novel furin inhibitors or modified forms of D6R may promote the reduction of immune tolerance and the elimination of infected hepatocytes in patients with chronic HBV infection.