Cyclophilins are involved in multiple steps of the hepatitis B virus (HBV) life cycle in hepatocytes—cyclophilin inhibitors reduce viral replication and HBV envelope protein production and secretion, researchers report in the February issue of Gastroenterology. The cyclophilin inhibitor alisporivir, combined with the HBV polymerase inhibitor, reduces markers of HBV infection and HBV replication in cells, revealing a possible new therapeutic approach for chronic hepatitis B.
Cyclophilins have peptidyl-prolyl isomerase activity, and catalyze the cis to trans conversion of proline-containing peptides and facilitate protein folding. There are several human genes that encode cyclophilins, including CYPA, CYPB, CYPC, and CYPD. Their products localize to different areas of the cell. For example, CYPA and CYP40 are present in the cytosol, CYPB and CYPC in the lumen of the endoplasmic reticulum, and CYPD is found in the mitochondria.
Cyclophilins regulate the life cycle of a range of viruses including HCV, HIV, vaccinia virus, coronaviruses, and polyomavirus BK, and are required for virus replication. CYPA is the main cyclophilin that regulates the life cycle of HCV; cyclophilins reduce HCV replication and secretion from infected cells.
Sandra Phillips et al investigated whether hepatocyte cyclophilins are involved in HBV replication, hepatitis B surface antigen (HBsAg) production, and secretion in liver-derived cell lines that produce full-length HBV and HBsAg particles.
They found that the cyclophilin inhibitor alisporivir reduced intracellular and secreted HBV DNA in liver cells lines in a dose-dependent manner. Knockdown of CYPA, CYPC, or CYPD significantly reduced levels of HBV DNA and secreted HBsAg—a marker of HBV infection.
Small molecule inhibitors of cyclophilins also reduced levels of HBsAg produced by cells, and caused a dose-dependent reduction in HBV DNA. The combination of alisporivir and telbivudine had greater antiviral effects than those of telbivudine or alisporivir alone. The authors propose that the cyclophilin inhibitors alisporivir and NIM811 block multiple cyclophilins, affecting not only HBV replication and HBsAg production, but multiple stages of the HBV life cycle.
CYPA is one of the most abundant cytosolic proteins (approximately 0.1% of cell proteins). Phillips et al showed that CYPA participates in HBV replication and envelope protein secretion from hepatocytes. They say that CYPA is important for the formation of intracellular, nucleocapsid-associated HBV DNA and viral secretion and for HBsAg secretion from cells.
The authors propose a new approach for treating chronic hepatitis B that involves a combination of a direct antiviral agent (such as the HBV-DNA polymerase inhibitors) and agents that act directly on liver cells, such as those that block cyclophilins.
Alisporivir is in development for the treatment of chronic hepatitis C. Phillips et al say that it has been evaluated in more than 2000 patients and seems to be well tolerated, with a better safety profile when given as interferon-free treatment than with interferon.
The authors conclude that combination treatment with an HBV nucleos(t)ide polymerase inhibitor plus a cyclophilin inhibitor would interfere with multiple sites of the HBV life cycle, reducing HBsAg production and secretion as well as blocking HBV entry into non-infected hepatocytes.