28 August 2007

HSP90, Cancer, and Sepsis

HSP90 is a heat shock protein--proteins in the cell that become more concentrated in reaction to cellular stresses, including heat. HSP90 also has normal, non-stress functions in the cell--particularly chaperone functions. As a chaperone, HSP90 helps to keep proteins from folding in aberrant and dysfunctional conformations.

HSP90 inhibitors have recently come into play for the treatment of malignancies. HSP90 tends to reduce (through re-folding and other pro-degradation processes) the concentration of apoptotic products coming from early cancer cells--allowing the cells to grow longer and become more difficult to treat with conventional cancer treatments. Inhibiting HSP90 leads to more apoptosis of cancer cells, and more effective cancer treatment.Researchers have recently begun to look at HSP90 inhibitors for treating sepsis and other conditions of extreme inflammation in the body.
Studies in an animal model of sepsis, a major cause of ICU patient death, indicate HSP 90 inhibitors help degrade proteins perpetuating inflammation, says Dr. John D. Catravas, director of the Medical College of Georgia Vascular Biology Center.

Results include restored lung function, reduced blood vessel leakage, which can lead to dangerous swelling in the lungs, and fewer byproducts of inflammation such as white blood cells, MCG researchers report in the American Journal of Respiratory and Critical Care Medicine, a journal of the American Thoracic Society.

...These manmade HSP 90 inhibitors work by attaching where the protein pair's energy source, called ATP, should be. The body appears to have an endogenous version, ADP, which has one less phosphate than ATP and binds at the same site, also opening the protein claws and sending the client protein toward degradation.

Getting down to the level of folding and re-folding of proteins is an important step for pharmacologists and protein scientists. This is where the rubber meets the road in cellular function. It should not go unsaid that there are important lessons here for nanotechnologists as well.

By understanding how to lock, unlock, and modify active sites of proteins--and controlling their energetics and shape--protein scientists are in essence bio-nanotechnologists.

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