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Shifting evolution into reverse promises cheaper, greener way to make new drugs
Date:3/23/2014

the development of life where early organisms were swimming in a primordial soup rich in organic material. In this environment, imagine that one of the species finds a use for the complex chemical compound A that gives it a competitive advantage. As a result, its population expands, consuming more and more compound A. Everything goes well until compound A becomes scarce. When that happens, individuals who develop an enzyme that allows them to substitute the still plentiful compound B for the scarce compound A gain a reproductive advantage and continue to grow while those who remain dependent on compound A die out. And so it goes until many generations later the survivors have developed multi-step chemical pathways to produce the molecules that they need to survive from the molecules available in their environment.

To test Bachmann's retro approach, the Vanderbilt chemists first identified the drug that they wanted to produce in this case didanosine, an anti-HIV drug sold under the trade names of Videx and Videx EC that is very costly to manufacture. Then they identified a similar "precursor" molecule that can be converted into didanosine when it is subject to a specific chemical transformation along with an enzyme capable of producing the type of transformation required.

Once they identified the enzyme, the researchers made use of the power of natural selection by making thousands of copies of the gene that makes the enzyme using a special copying technique that introduces random mutations.

The mutant genes were transferred into the gut bacteria E. coli in order to produce the mutant enzymes and placed into different "wells." After the cells were broken open and the contents mixed with the precursor compound, the amount of didanosine, in each well was measured. The researchers selected the enzyme that produced the greatest amount of the desired drug and then made enough of this optimized enzyme for the next step.

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Contact: David Salisbury
david.salisbury@vanderbilt.edu
615-343-6803
Vanderbilt University
Source:Eurekalert

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