Unlock secrets of disease proteins to target drugs better

October 21st, 2008 - 1:33 pm ICT by IANS  

Washington, Oct 21 (IANS) Drug molecules seldom act on a single protein but on protein complexes and networks, an understanding of which should lead to better targeting of drugs.New research into how proteins in human cells ‘talk’ to one another is making a better understanding possible of how drug molecules work and should result in more effective therapies, according to a leading European scientist.

“Most of the time the mechanism of action of drugs is ill understood and we often do not even know the primary target of the drugs we swallow daily,” said Giulio Superti-Furga, Centre for Molecular Medicine of the Austrian Academy of Sciences.

“We do not know how these drugs work at the molecular level, and side effects can have serious consequences,” he added.

Our lack of understanding of the way that drugs work is illustrated by the fact that around four in 10 drugs currently on the market were developed for one use but were subsequently found to be better for a different condition.

Superti-Furga was speaking at the European Science Foundation’s 3rd Functional Genomics Conference in Innsbruck, Austria, held early this month, according to a release of the European Science Foundation

Functional genomics describes the way in which genes and their products, proteins, interact together in complex networks in living cells. If these interactions are abnormal, diseases can result.

The Innsbruck meeting brought together more than 450 scientists from across Europe to discuss recent advances in the role of functional genomics in disease.

Researchers like Superti-Furga are taking a taking a ‘proteomics’ approach to understanding precisely how certain proteins that are key drug targets organise themselves in the cell, and how they make complex interactions with often dozens of other proteins. “Proteomics is a way of joining the dots together to give us the bigger picture,” he said.

Superti-Furga’s team has been investigating a particular enzyme, a tyrosine kinase called Bcr-Abl, which is involved in leukaemia. A drug is available that acts on the enzyme, but it eventually loses its efficiency as patients become resistant to it.

“We need to understand the relationship between the drug and the target,” said Superti-Furga. “Can we understand the 3-d protein as a molecular machine much better?”

Superti-Furga’s lab in Vienna has used a range of proteomics techniques to isolate the enzyme and dissect its constituent parts. They discovered that the protein exists as a complex of some 46 separate components and operates as a giant molecular machine, with each part in close communication with the others.

“It is clear that tyrosine kinase inhibitors do not simply inhibit the enzyme, but rather remodel the machine,” Superti-Furga said. “If we can understand how these proteins interact, people might say we should target this pathway or that network; by targeting multiple nodes we will be able to maximise the good side effects against the bad side effects.”

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