The investigational drug VX-497 may have potent, broad-spectrum antiviral activity, according to laboratory results presented by scientists from Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) at the 12th International Conference on Antiviral Research held this week in Jerusalem, Israel. VX-497's activity against viruses in cell culture was compared to that of the antiviral compound ribavirin, both alone and in combination with interferon–alpha. Vertex is evaluating VX-497 in Phase II clinical trials for HCV infection and as an immunosuppressant for psoriasis.
VX-497 is a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH), a human enzyme that is essential for the de novo production of guanosine nucleotides (for example, GTP)-one of the building blocks of RNA and DNA. Inhibition of IMPDH may be an effective strategy for blocking the rapid proliferation (growth) of certain cell types which uniquely depend upon this de novo pathway--such as B and T lymphocytes--as well as blocking viral replication, which is often more dependent on the de novo pathway than on the alternative "salvage" pathway of nucleotide biosynthesis used by most human cells.
In one study comparing the activity of VX-497 versus ribavirin against selected DNA and RNA viruses in vitro, VX-497 was found to be 15-to 186-fold more potent than ribavirin against hepatitis B virus, human cytomegalovirus, respiratory syncytial virus, herpes simplex virus type 1, parainfluenza-3 virus, and Venezuelan equine encephalitis virus. Preliminary data suggests VX-497 may be more potent than ribavirin against bovine viral diarrhea virus and as potent as ribavirin against dengue virus.
In another study, using cells infected with encephalomyocarditis virus (EMCV), VX-497 was shown to have 15-to 40-fold more potent antiviral activity in combination with interferon-alpha, when compared to a combination of ribavirin plus interferon-alpha. Ribavirin is marketed in the United States as an inhaled antiviral agent for treatment of respiratory syncytial virus and as an oral antiviral agent, in combination with interferon-alpha, for the treatment of chronic hepatitis C (HCV) infection.
Vertex scientists also presented the first three-dimensional atomic X-ray crystal structure of ribavirin bound to the IMPDH enzyme, providing important insights into one of the targets of ribavirin's action. The structure of the complex, which was solved at a resolution of 1.85 angstroms, is the highest resolution of the structure of IMPDH reported thus far.