Getting to grips with the complexity of disease proteins

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Getting to grips with the complexity of disease proteins

http://www.eurekalert.org/pub_releases/2008-10/esf-gtg102008.php

Drug molecules seldom act simply on one protein but on protein

complexes and networks. A deeper understanding of these 'cooperative

assemblies' should lead to better targeting of drugs

New research into how proteins in human cells interact and 'talk' to

each other is leading to a better understanding 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, " Professor Giulio Superti-Furga of the Centre for

Molecular Medicine of the Austrian Academy of Sciences said. " We do

not know how these drugs work at the molecular level, and side

effects can have serious consequences. "

Superti-Furga was speaking at the European Science Foundation's 3rd

Functional Genomics Conference in Innsbruck, Austria, held on 1-4

October. 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.

Our lack of understanding of the way that drugs work is illustrated

by the fact that around four in ten drugs currently on the market

were developed for one use but were subsequently found to be better

for a different condition.

Researchers such as 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 aid. " So

drugs do not simply ablate things, they interfere with the equilibria

of networks. If we can understand how these proteins interact, in the

future 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. "

The team has also been developing methods to understand how the human

body can recognise invading foreign genetic material – comprising

nucleic acids – from bacteria or viruses for example, and distinguish

it from its own, innate genetic material.

It is thought that proteins in the human cell can tell if a sequence

of nucleic acids is from an invading organism. To try to identify

these proteins the research team has developed a technique to test

which proteins in a cell bind specifically to foreign nucleic acids.

They have also observed which genes in the cell are switched on

or 'up regulated' when foreign genetic material is present – and

whether the proteins that are encoded by these genes are the same as

those that bind to the material. A number of candidate proteins have

emerged from this process and are undergoing further study.

The work will provide important insights into how the body defends

itself against invading organisms.