The new approach to modifying enzymes to produce more selective catalysts is faster than rational enzyme design and can be done in a high throughput manner giving superior efficiency chemical transformations that control the three-dimensional construction of drug targets. Controlling the 3D shape of drug molecules is essential to their activity in the body. The slightest change in the configuration of a molecule can disrupt its interaction with the body destroying the therapeutic value of the drug. Configuration changes to a drug molecule can also lead to very serious side effects, such as those found with Thalidimide.

Researchers at the University of Leeds' Astbury centre, enzymologist Dr Alan Berry and chemist Professor Adam Nelson collaborated on the project to evolve a catalyst to make analogues of GlaxoSmithKline / Biota's anti-flu drug Relenza (zanamivir).

Talking to DrugResearcher.com, Professor Adam Nelson, deputy Director of the Astbury Centre and Professor of Chemical Biology at Leeds University, described the project as: "research that could only have happened in a collaboration."

The evolution of the enzyme involved using standard molecular biology procedures to create mutations in the enzyme, which were then grown on Agar plates before robotically being placed in a 96-well plate.

The enzymes were then tested for their activity in the desired reaction and the reaction progress followed by a plate reader looking for an easily observable change in the physical properties of the reactants, for instance a decrease in the fluorescent signal.

The reaction studied in this case was the aldol coupling of N-acetyl mannosamine with pyruvate to produce the sialic acid N-acetylneuraminic acid. Sialic acids are essential components of the complex carbohydrate molecules that play pivotal roles in a variety of biological functions and are often used by pathogens and parasites in the invasion, infection and survival in the body.

Sialic acid mimics have been found to be important chemotherapeutic agents, most notably anti-influenza drugs, such as Relenza and Roche's Tamiflu (oseltamivir).

Professor Nelson said: "you can evolve and screen a generation of an enzyme in two weeks, you probably need to go to the fourth or fifth generation to find the best enzyme for the job."

The reactions were carried out in potassium phosphate buffered water at pH 7 and at room temperature, which will be a benefit in the synthesis of new drugs due to the ever-increasing pressures to develop more environmentally friendly and energy efficient processes.

Professor Nelson said: "Directed evolution could help simplify the production process for many drugs already on the market, but it's unlikely to be used in this way as a new method of synthesis requires approval even for an existing drug." "In the future, drug design is likely to focus more and more on directed evolution, with a big increase in the number of bio-engineered catalysts created for drug development."