A compound tested by UT Southwestern Medical Center investigators destroys several viruses, including the deadly Spanish flu that killed an estimated 30 million people in the worldwide pandemic of 1918.
This lead compound -- which acts by increasing the levels of a human antiviral protein -- could potentially be developed into a new drug to combat the flu, a virus that tends to mutate into strains resistant to anti-influenza drugs.
"The virus is 'smart' enough to bypass inhibitors or vaccines sometimes. Therefore, there is a need for alternative strategies. Current drugs act on the virus, but here we are uplifting a host/human antiviral response at the cellular level," said Dr. Beatriz Fontoura, associate professor of cell biology and senior author of the study available online in Nature Chemical Biology.
According to National Institutes of Health, influenza hospitalizes more than 200,000 people in the U.S. each year, with about 36,000 fatalities related to the illness. Worldwide, flu kills about 500,000 people annually.
In the latest cell testing, the compound successfully knocked out three types of influenza as well as a smallpox-related virus and an animal virus. Because of the highly contagious nature of the 1918 flu, those tests took place at Mount Sinai School of Medicine in New York, one of the few places that stores and runs tests on that flu strain.
The compound is among others that the research team is testing that induce an infection-fighting human protein called REDD1. Until this study, researchers had not demonstrated that REDD1 had this important antiviral function.
"We've discovered that REDD1 is a key human barrier for infection," said Dr. Fontoura, "Interestingly, REDD1 inhibits a signaling pathway that regulates cell proliferation and cancer."
The UT Southwestern-led research team tested 200,000 compounds for those that would inhibit flu virus infection. A total of 71 were identified.
Using the two most promising compounds, researchers at UT Southwestern and colleagues at Mount Sinai next will work to strengthen their potencies for further testing. Dr. Fontoura said it can take more than 10 years before successful compounds are developed into drugs.
UT Southwestern researchers involved in the study were lead author Miguel Mata and Neal Satterly, both graduate students in Dr. Fontoura's laboratory; Dr. Doug Frantz, former assistant professor of biochemistry; Shuguang Wei, a senior researcher in biochemistry; Dr. Noelle Williams, associate professor of biochemistry; Samuel Pena-Llopis, assistant instructor in developmental biology; Dr. James Brugarolas, assistant professor of internal medicine; Dr. Christian Forst, assistant professor of clinical sciences; Dr. Michael White, professor of cell biology; and Dr. Michael Roth, professor of biochemistry.
The research was supported by nine National Institutes of Health grants and by the Diane and Hal Brierley Distinguished Chair Fund.
- Miguel A Mata, Neal Satterly, Gijs A Versteeg, Doug Frantz, Shuguang Wei, Noelle Williams, Mirco Schmolke, Samuel Peρa-Llopis, James Brugarolas, Christian V Forst, Michael A White, Adolfo Garcνa-Sastre, Michael G Roth, Beatriz M A Fontoura. Chemical inhibition of RNA viruses reveals REDD1 as a host defense factor. Nature Chemical Biology, 2011; 7 (10): 712 DOI: 10.1038/nchembio.645
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