Sunday, November 29, 2009

Mode of action of tetrathiomolybdate (a drug for Wilson's disaese) established ?

We know that Ammonium tetrathiomolybdate ([NH4]2MoS4), was first used therapeutically in the treatment of copper toxicosis in animals. It was then introduced as a treatment in Wilson's disease, a hereditary copper metabolism disorder, in humans; it acts both by competing with copper absorption in the bowel and by increasing excretion. It has also been found to have an inhibitory effect on angiogenesis, potentially via the inhibition of Cu ion dependent membrane translocation process invovling a non-classical secretion pathway. This makes it an interesting investigatory treatment for cancer, age-related macular degeneration, and other diseases featuring excessive blood vessel deposition. Though the activity was established mode of action was to be established. Now researchers from Northwestern University , have achieved something which was eluding so for. As per the claim by the researchers, the three-dimensional structure of TM bound to copper-loaded metallochaperones. The drug sequesters the chaperone and its bound copper, preventing both from carrying out their normal functions in the cell. For patients with Wilson disease and certain cancers whose initial growth is helped by copper-dependent angiogenesis, this is very promising. O'Halloran and his research team studied the copper chaperone protein Atx1, which provides a good model of copper metabolism in animal cells.

The drug brings three copper chaperones into close quarters, weaving them together through an intricate metal-sulfur cluster in a manner that essentially shuts down the copper ferrying system.

The nest-shaped structure of the metal-sulfur cluster discovered by the researchers was completely unanticipated. The sulfur atoms in the tetrathiomolybdate bound to the copper atoms to form an open cluster that bridged the chaperone proteins. In this manner, three copper proteins were jammed onto one thiomolybdate. More interestingly the structure of the complex has been concluded by X-ray studies. Based on the structure and additional experiments, the scientists propose that the drug inhibits the traffic of copper within the cell because of its ability to sequester copper chaperones and their cargo in clusters, rendering the copper inactive.

Copper also is an important cofactor for tumor angiogenesis, the process of growing new blood vessels to feed the tumor. Researchers believe this is why tetrathiomolybdate has shown promise as an anti-cancer drug. Hope the clinical trials (phase II) of tetrathiomolybdate (as anticancer drug) a success and wide applications of this drug (as amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis and Alzheimer's disease, primary pulmonary hypertension and left ventricular hypertrophy) will help patients to breathe a sigh of relief...

Ref :

No comments: