2006 - 2007
24-dehydrocholesterol reductase(DHCR24) inhibitor suppresses HCV replication
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B) Grant-in-Aid for Scientific Research (B)
- Grant number
- 18390146
- Japan Grant Number (JGN)
- JP18390146
- Grant amount
-
- (Total)
- 16,830,000 Japanese Yen
- (Direct funding)
- 14,700,000 Japanese Yen
- (Indirect funding)
- 2,130,000 Japanese Yen
Hepatitis C virus (HCV) frequently causes chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). We previously established the conditional full-length HCV gene expressing HepG2 cells and observed their increased tumorigenicity after 44 days passage (RzM6 44 days cells). In order to clarify the existence of antigens whose expression level has been changed according to the tumorigenicity, we established the monoclonal antibodies (MoAbs) against these cells. Over one thousand monoclonal antibodies were established, and their reactivities to RzM6 44 days cells were characterized. Several clones with significantly different reactivity to these cells, we first characterized clone 2-152, and it recognized approximately 55 killodalton (kDa.) molecule (p55). Therefore, we identified p55 molecule by MALDI-TOF/MS as 24-dehydrocholesterol reductase (DHCR24).
DHCR24 is a enzyme in the cholesterol biosynthetic pathway. U18666A is an inhibitor of DHCR24 and suppresses replication of the hepatitis C virus (HCV) replicon cells. We investigated the anti-HCV effect of U18666A against intact HCV using chimeric mice with humanized liver infected with HCV genotype 1a or 1b. We administered U18666A into HCV infected chimeric mice and succeeded in reducing the HCV RNA levels in serum and liver to 1/10-1/100 of the levels prior to the 8 day treatment. Furthermore, combined treatment with pegylated interferon reduced the HCV RNA levels to less than 1/1000 of the control levels. We strongly suggest that suppression of DHCR24 reduces HCV replication, and therefore that the DHCR24 inhibitor is potentially a novel drug in the treatment of HCV infection.
DHCR24 is a enzyme in the cholesterol biosynthetic pathway. U18666A is an inhibitor of DHCR24 and suppresses replication of the hepatitis C virus (HCV) replicon cells. We investigated the anti-HCV effect of U18666A against intact HCV using chimeric mice with humanized liver infected with HCV genotype 1a or 1b. We administered U18666A into HCV infected chimeric mice and succeeded in reducing the HCV RNA levels in serum and liver to 1/10-1/100 of the levels prior to the 8 day treatment. Furthermore, combined treatment with pegylated interferon reduced the HCV RNA levels to less than 1/1000 of the control levels. We strongly suggest that suppression of DHCR24 reduces HCV replication, and therefore that the DHCR24 inhibitor is potentially a novel drug in the treatment of HCV infection.
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- Grant number : 18390146
- Japan Grant Number (JGN) : JP18390146