Progenics Pharmaceuticals Discovers the First Liver-Specific Receptor for Hepatitis C Virus
Tuesday April 1, 5:00 am ET
TARRYTOWN, N.Y.--(BUSINESS WIRE)--April 1, 2003--Progenics Pharmaceuticals (Nasdaq:PGNX - News)
Receptor may reveal how HCV infects the liver and provide a new therapeutic drug target -
Scientists from Progenics Pharmaceuticals (Nasdaq: PGNX - News) may have solved a longstanding riddle concerning hepatitis C disease: How does the virus target the liver for infection? Researchers today reported discovering the first-ever liver-specific receptor, called L-SIGN, for hepatitis C virus (HCV). The Company also reported the identification of specific inhibitors, including a monoclonal antibody, that blocked HCV from binding to the L-SIGN receptor. Preventing HCV from binding L-SIGN on liver cells represents a new and targeted strategy for treating this serious disease. The studies are reported in a paper published today in the Proceedings of the National Academy of Sciences USA. The publication is scheduled to be available online this week in the PNAS Early Edition at pnas.org.
"In recent years, various cellular receptors for HCV have been proposed, but until now, none had been found that occurred specifically in the liver and was capable of binding with HCV," said the paper's senior author William C. Olson, Ph.D., Progenics' Vice President of Research and Development. "As we reported in today's PNAS article, L-SIGN efficiently binds and captures naturally occurring hepatitis C virus particles. We further demonstrated that L-SIGN binds to a viral protein called E2 that is present on the surface of the HCV particle. L-SIGN is found on specialized liver cells that form a barrier between the bloodstream and the surrounding liver tissue. These cells are the first to contact HCV as it enters the liver via the bloodstream. Thus, L-SIGN is uniquely positioned to capture blood-borne virus and concentrate it in the liver, thereby potentially facilitating initial and subsequent rounds of infection."
HCV infection afflicts nearly 3% of the world's population and causes serious liver disease, including cirrhosis and cancer. No vaccine is available to prevent new infections. Current therapies are largely non-specific, effective in only about half of all cases, and have a high relapse rate. New treatment strategies are urgently needed to combat this debilitating disease.
"The L-SIGN receptor is abundantly expressed on endothelial cells of the liver and binds to the envelope glycoprotein E2 of HCV," explained Tatjana Dragic, Ph.D., Assistant Professor of Microbiology and Immunology, Albert Einstein College of Medicine and co-author of the manuscript. "Viruses often make use of cellular receptors to target a specific tissue for infection. For example, the human immunodeficiency virus (HIV) targets the CD4 receptor on immune system cells. As the first step of viral entry, the HIV glycoprotein gp120 attaches to cellular CD4. HCV's E2 glycoprotein may serve as the functional equivalent of HIV gp120. Our paper shows that E2 bound to the L-SIGN receptor as a potential means of targeting the liver. The research further demonstrated that HCV bound to a related receptor, known as DC-SIGN, that is expressed on dendritic cells, which are specialized cells of the immune system. L-SIGN and DC-SIGN are also expressed in placental tissue, and thus the findings may also explain why HCV is readily passed from mothers to their newborn children."
"Our previous discoveries of the cellular receptors utilized by HIV have translated directly into novel therapeutic agents, and we are eager to leverage this expertise for HCV therapy," added Dr. Olson. "We have shown that HCV binding to L-SIGN can be blocked in the laboratory using specific inhibitors, including monoclonal antibodies. In addition, HCV appears to bind L-SIGN at a site different from that of its natural ligand (ICAM-3), which is a protein that mediates adhesion between cells. Thus, it may be possible to block HCV without blocking the natural activity of L-SIGN. These findings provide proof-of-concept for targeted therapy. Our current goals are to develop increasingly potent and drug-like inhibitors while concurrently exploring the role of L-SIGN in natural infection." |
