Researchers are making gains in determining exactly what role chaperone proteins play in the formation of many diseases. The emerging paradigm shifter is that chaperone binding is regulated through their interactions with client proteins first, and then other cooperative functions with different chaperone molecules. This new research already has the scientific community abuzz, talking about the new tools available to deal with viruses, bacteria, and infectious diseases. Chaperone proteins, aka heat-shock proteins, exist naturally inside cells to prevent proteins from unfolding and becoming tangled up with other proteins forming aggregates. What researchers at the Institute of Cancer Research in Sutton, UK have discovered is that at least one distinct family of chaperone proteins (Figure 1) have more specialized roles than previously observed, and could be the key to treating a range of diseases, including breast cancer (pictured above). The evidence, presented by Paul Workman, the director of the Cancer Therpaeutics Unit at the Institute of Cancer Research, put their hope onto a chaperone protein called heat shock protein 90 (Hsp90). Different families of chaperones can function in different organelles [1]. And so while the variety of chaperone proteins examined have a similar function, one thing that has emerged from Workman’s research are how the different specificities of Hsp90 are useful when dealing with certain infectious diseases [2].

Figure 1. Families of Chaperone Proteins with Stress Cues (Image courtesy:

hsp family

HSP90 Inhibitors

What researchers found was that by inhibiting (blocking) this receptor using a known Hsp90 inhibitor, called 17-AAG, led to a diminished rate of infection of malaria and lessened the spread of breast cancer. The inhibitor has worked mainly due to the ability of viruses to infect specific cells based upon their having certain receptors on the cellular surface. In some cases, such as malaria, the ability of 17-AAG to occupy the binding sites prevents these surface interactions from taking place, thereby decreasing the chances the malaria virus will be absorbed into the cell.

In the case of breast cancer, Hsp90 inhibitors could overcome breast cancer by offering clinicians a way to disrupt the body's ability to synthesize estrogen if the cancer forms a resistance to more commonly used estrogen-blocking drugs. Early fears that the drug would be toxic because it works against so many different targets at once never materialized. The thousands of research papers in the literature have helped to catapult the approximately twenty Hsp90-targeting drugs that are in clinical trials today. Inhibitors of this chaperone are also showing promise as anti-influenza agents [3].

Hsp90 has the ability to be applied broadly due to their association with many proteins, including retroviruses, steroid hormones, protein kinases, actin, tubulin, have all been demonstrated. Because the chaperone molecule has a natural ability to target may types of client cells, has led to some calls of resistance for their use as treatments in order to leave time to work out any kinks with their functionality.

If you ask Paul Workman, he'll tell you that the road to drug discovery is, inherently risky, even if you have a well-validated target. Many people, including people in industry, are saying much of the early risk has to be taken up by academic groups, to the point where industry has the confidence to take it on."

Protein Aggregates Cause Destructive Human Diseases

Chaperones become activated by some environmental stress response, such as an increase in body temperature. When a cell's quality controls fails, proteins aggregate with misshappen folds building up in the affected cell until, eventually, causing cell death [4]. The brain is extremely sucesptible to protein aggregation, and is the primary cause of dementia and Hunington's Disease.

Researchers based out of the Institute of Cancer Research in the UK say similar drugs may also be possible to boost the Hsp90 chaperone function for patients suffering from Alzheimer's and Parkinson's disease. But some say it's too risky and out of the box, since Hsp90-inhibitors are basically the master-switch to many functions and their use has not been widely tested. But, at least in theory, it would fit within the paradigm of current consensus that the origin of disease suggests that certain proteins in the brain become inappropriately folded over time. And so boosting the presence of certain protein specific chaperones could one day prove to be a helpful way to improve treatment options for certain side effects for both diseases, such as brain function, muscle movement and memory. And although no HSP90 inhibitors have been approved by the FDA, as of yet, several are being tested in clinical trials for Multiple Myeloma.

Multiple Myeloma

This table lists several HSP90 inhibitors that have been or are being tested in clinical trials for multiple myeloma. To date, none of these agents has been approved by the FDA for treatment of multiple myeloma.

Research Name Generic Name Trade Name(s) Drug Type
HSP90 Inhibitors KOS-1022 (also called 17-DMAG) Alvespimycin Small molecule
KOS-953 (also called 17-AAG) Tanespimycin Small molecule
AUY922 Luminespib Small molecule

Chaperone proteins could be the key to treating a variety of debilitating diseases, including some types of cancers. But are they too unorthodox given their ability to target many cells to risk precious research dollars on? Is the medical community being too cautious to embrace new options that may improve their patient's health?

What do you think?

Let us know in the comments.


[1,4] Molecular Biology of the Cell. by John Wilson, Tim Hunt; Garland Science, 4th edition, 2002. Page 1452-1453.

[2] Proteins chaperone drugs in development. by Daniel Cressey. Nature. August, 2011.

[3] Mechanisms of Protein Folding. by R.H. Pain. Oxford University Press. 2013. Pages 201-204, 214.