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New high-res structure will boost AIDS, cancer drug development

By Mike Nagle , 23-Oct-2007

By solving the structure of a mammalian heat shock protein (HSP90) for the first time, a US scientist may have unlocked the door to better drugs to fight a myriad of diseases, such as AIDS, sepsis, certain cancers and Alzheimer's.

Dr Dan Gewirth, of the Hauptman-Woodward Institute (HWI) in New York, has published the world's first high-resolution 3D structure of GRP94, and thus confirmed his earlier hypothesis that this protein is a member of the HSP90 family. The X-ray diffraction study is published in the latest edition of Molecular Cell.

 

 

 

The HSP90 family of proteins are chaperones - they help other proteins achieve their active shapes - and are already being widely investigated by the pharma industry as they are key players in cell regulation and recognition. For example, HSP90 inhibitors could be used to treat some cancers while drugs that stimulate HSP90 action may be appropriate therapies for diseases involving protein folding, such as cystic fibrosis, prion diseases, and Alzheimer's Disease.

 

 

 

"Our work opens the door to a more intensive evaluation of this protein both from a mechanistic as well as a therapeutic point of view." said Gewirth.

 

 

 

"In addition to aiding our understanding of the fundamental biology of chaperone-mediated protein folding, this work lays the foundation for the design of drugs that specifically target individual members of the HSP90 family," he continued.

 

 

 

Currently, HSP90 drugs are broad-spectrum inhibitors of many, if not all, HSP90 proteins and this can lead to unwanted side-effects. The high resolution structure could now be used to generate computational models of other members of the protein family and unlock the door to designing specific drugs that target only one protein.

 

 

 

Also, the fact that it is a mammalian structure should mean future research will more accurately reflect what happens in humans. Other HSP90 structures have been solved from either bacteria or yeast but human energy production and consumption rates are more similar to those found in the GRP94 proteins than to these more widely studied HSP90 proteins. This means that the insights gained by studies of GRP94 works will have more direct applications to human diseases.

 

 

 

The work could also have a financial impact on the pharma industry.

 

 

 

"This will spur a new line of inquiry into GRP94. While this work is its infancy, medicinal chemists will be interested in developing GRP94-targeted drugs," Gewirth added.

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