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Another class of drugs, human tissue transglutaminase inhibitors, has been identified as a potential treatment.
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abstract
Human tissue transglutaminase (TGM2) is a calcium-dependent crosslinking enzyme involved in the posttranslational modification of intra- and extracellular proteins and implicated in several neurodegenerative diseases. To find specific inhibitors to TGM2, two structurally diverse chemical libraries (LOPAC and Prestwick) were screened. We found that ZM39923, a Janus kinase inhibitor, and its metabolite ZM449829 were the most potent inhibitors with IC(50) of 10 and 5 nM, respectively. In addition, two other inhibitors, including tyrphostin 47 and vitamin K(3), were found to have an IC(50) in the micromolar range. These agents used in part a thiol-dependent mechanism to inhibit TGM2, consistent with the activation of TGM2 by reduction of an intramolecular disulfide bond. These inhibitors were tested in a polyglutamine-expressing Drosophila model of neurodegeneration and found to improve survival. The TGM2 inhibitors we discovered may serve as valuable lead compounds for the development of orally active TGM2 inhibitors to treat human diseases.
press release: Duke team finds compounds that prevent nerve damage
DURHAM, N.C. — Duke University Medical Center scientists have made a significant finding that could lead to better drugs for several degenerative diseases including Huntington's disease and Alzheimer's disease. Compounds that block the activity of a specific enzyme prevented brain injury and greatly improved survival in fruit flies that had the same disease process found in Huntington's disease.
"We were able to prevent Huntington's disease-like illness in mutant fruit flies by giving them orally active transglutaminase inhibitors," said Charles S. Greenberg, M.D., a Professor of Medicine and Pathology at Duke University Medical Center and senior author of the paper. The drug blocks the action of an enzyme called tissue transglutaminase (TGM2). TGM2 may damage cells by forming strong bonds between proteins. Such bonding is beneficial for blood clotting which happens outside of cells, but if this type of bonding occurs inside cells, it can be harmful, Greenberg said.
The study appears in the current issue of Chemistry and Biology.
Huntington's disease causes uncontrolled movement and mental deterioration that develops later in life, and though there is no cure, people can get tested to learn whether they have the gene that causes the devastating illness, Greenberg said.
Alzheimer's disease, Parkinson's disease and polyglutamine diseases including Huntington's disease may possibly be improved with the same compounds, said Thung S. Lai, Ph.D., lead author and a Duke Associate Professor of Medicine. "Our findings may also help to develop drugs that block the pathology related to transglutaminase's action. That action has been linked to the development of tissue fibrosis, organ failure and aging."
While these compounds were promising in the animal system, they are several years away from entering any human trials, Greenberg said. "We will be studying these compounds in diseases in which TGM2 produces tissue injury."
For the study, Lai painstakingly screened 2,000 compounds. Only two groups of drugs were found to be effective TGM2 inhibitors. Some of the most potent TGM2 inhibitors were given to the fruit flies along with their food.
The most effective compound was a kinase inhibitor, a drug that had been developed several years ago for another purpose. The other beneficial compounds fell into a category of drugs that attack a sulfhydryl group in a protein.
The next step is to use the effective compounds as the backbone for developing even more effective drugs, Lai said. The scientists plan to test whether the TGM2 inhibitors they identified would prevent the fibrous tissue process that causes chronic renal, vascular and lung disease.
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The work was funded in part by National Institutes of Health grants. This study required extensive teamwork between several departments at Duke and a long-time collaborator at Wake Forest University.
Source: Chemistry and biology 2008 Sep 22;15(9):969-78.
Printed: 11 Sep 2010
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Article posted to www.HDlighthouse.org on: 09-27-2008
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