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Sep 29, 2008

Antiobesity Drugs Shown to Inhibit Viral Infection

  • A group of scientists say that using existing antiobesity drugs aimed at fatty acid metabolism can reduce viral replication. This finding could lead to new treatments against viruses such as influenza, hepatitis, and HIV, which use fatty acids to build outer coatings that help them penetrate human cells.

    Researchers combined drug discovery technologies to capture the exact concentrations and fluxes of interchangeable molecules within the metabolic chain reactions that convert sugars into fatty acids.

    “Using new fluxomic techniques, our study reveals that viral infection takes control of cellular metabolism and drives, among other things, marked increases in fatty acid synthesis,” points out Joshua Munger, Ph.D., assistant professor of biochemistry and biophysics at the University of Rochester Medical Center.

    The researchers were studying metabolic flux in human cells infected by human cytomegalovirus (HCMV). They chose HCMV because it serves as a model for processes in many enveloped viral infections and in cancers. HCMV replicates in a variety of human cell types including fibroblasts, which were used in this research.

    The team created a stable, isotope-labeled version of glucose, which was then metabolized by cells in a similar fashion as unlabeled glucose. Liquid chromatography and mass spectrometry were then employed to track the isotope label as it spread through the metabolic network.

    Next, they used drugs known to inhibit enzymes that build fatty acids, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), to determine whether HCMV-induced fatty acid production was necessary for enveloped viruses to make copies of themselves.

    Treatment (10 mg/mL) with 5-tetradecyloxy-2-furoic acid (TOFA) resulted in a more than 1,000-fold reduction in HCMV replication. Trans-4-carboxy-5-octyl-3-methylene-butyrolactone (C75) resulted in a more than 100-fold effect at the same dose, the scientists report.

    To investigate whether this requirement extended to other enveloped viruses, the team measured influenza A replication in the presence of the same TOFA and FAS inhibitors and found similar reductions in replication.

    The researchers acknowledge that extensive clinical testing would be needed to draw conclusions about the safety of TOFA and C75 as antiviral treatment. That said, the team took an early look at toxicity, exposing uninfected fibroblasts to C75 or TOFA for 96 hours. They found that the drugs blocked HCMV replication without causing cell toxicity or apoptosis. Researchers from the University of Rochester Medical Center and Princeton University worked together on the study. Results are published today in Nature Biotechnology.



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