Compound kills highly contagious flu strain by activating antiviral protein

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.

Provided by UT Southwestern Medical Center (news : web)

Modified genetic alphabet: Chemical evolution generates bacterial strain with artificial nucleotide in its genome

 Evolution is based on heredity, changes to the genetic material (mutation), and the natural selection of those organisms that are best suited to the given environmental conditions. An international team led by Rupert Mutzel at the Freie Universität of Berlin has now successfully emulated one particular evolutionary process in the laboratory. As the researchers report in the journal Angewandte Chemie, they were able to generate a bacterial strain whose genetic material contains an artificial building block in place of a natural one. Their success results from a special automated cultivation technique.

DNA, the carrier of the genetic information of all cells, is based on a code consisting of four “letters”, the bases adenine, cytosine, guanine, and thymine. Thanks to their new artificial evolution process, the scientists have now been able to grow bacteria in which the thymine of DNA has been replaced with an analogue, the base 5-chlorouracil. This synthetic component is poisonous to other organisms.

The researchers started with a genetically modified strain of the bacterium Escherichia coli that is no longer capable of producing thymine. These microorganisms were cultivated over many generations in the presence of increasing amounts of chlorouracil in a specially built apparatus. Whenever the size of the population sank below a certain level, the bacteria were given a brief dose of a chlorouracil-free, thymine-containing medium to give them a chance to recover. The concentration of chlorouracil was automatically increased whenever genetic variants of the bacteria that better tolerated this substance were produced.

In this way, the cells were always exposed to a quantity of chlorouracil that was just barely tolerable. After about 1000 generations, the microorganisms had adapted to the altered environmental conditions, that is, the presence of chlorouracil instead of thymine. They were able to build up their DNA with chlorouracil in place of thymine. Analysis of the genome showed that the process of adaptation resulted in many changes to the genetic material of the bacteria.

“Our results demonstrate the success of our evolutionary cultivation strategy,” says Mutzel. “In this way it should be possible to develop microorganisms that can convert chemical intermediates to pharmaceuticals or break down environmental pollutants.” Microorganisms that have DNA with synthetic building blocks may also be useful in hindering the spread of purposely or accidentally released modified cells in the environment. Such microorganisms would also be incapable of exchanging genes with their natural relatives.

More information: Rupert Mutzel, Chemical Evolution of a Bacterium's Genome, Angewandte Chemie International Edition 2011, 50, No. 31, 7109–7114, Permalink to the article: http://dx.doi.org/ … ie.201100535

Provided by Wiley (news : web)