Anti-Obesity Drugs Could Fight Viral Infections
Drugs used to treat obesity may be effective against a wide range of viral infections such as the flu, hepatitis, and even HIV, say researchers from the University of Rochester Medical Center and Princeton University.
In cellular metabolism, glucose can be converted into fatty acids — a process known as fatty acid biosynthesis. Fatty acid biosynthesis is not essential in humans, but many viruses use these fatty acids to build their viral envelopes, or outer coatings, which help the viruses penetrate and infect human cells.
For the new study, published Sept. 28 in the journal Nature Biotechnology, the researchers developed techniques to monitor cell metabolism as human cells become infected by a virus called human cytomegalovirus (HCMV). HCMV serves as a model for the processes that occur in many enveloped viral infections and in cancer.
“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,” study author John Munger, assistant professor of biochemistry and biophysics at the University of Rochester Medical Center, said in a medical center news release. “We also found that if you target these increases in fatty acid metabolism using existing anti-obesity and anti-metabolism drugs, you inhibit viral replication.”
Using their technique, the researchers tracked isotope-labeled glucose as it spread during cellular metabolism. They measured the impact that infection with HCMV had on the speed at which the labeled glucose spread.
To determine whether interfering with fatty acid biosynthesis could stop viral replication, the researchers studied the effects of drugs that inhibit acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), which are enzymes that build fatty acids. These drugs are currently used to treat obesity and high cholesterol.
Treatment with 5-tetradecyloxy-2-furoic acid (TOFA), an ACC inhibitor, resulted in a more than thousand-fold reduction in HCMV replication. And treatment with C75 (trans-4-carboxy-5-octyl-3-methylene-butyrolactone), an inhibitor of FAS, resulted in a more than 100-fold reduction in the virus’ replication.
To see if the drugs would impact the replication of other enveloped viruses, the researchers measured the replication of influenza A in the presence of the same drug. They found similar reductions in replication.
“Recent studies have shown that fatty acid biosynthesis is important for the replication of diverse enveloped viruses,” said Munger. “The replication of both hepatitis C and HIV, for example, has been linked recently with lipid synthesis, reinforcing our approach and its importance. Lastly, viral infection also clearly upregulates glycolysis, a marker for tumor growth, which is just the latest in the longstanding connection between viruses and cancer. Hopefully, our work will at some point provide insight into the metabolic manipulations seen in cancer as well.”