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Duke researchers ID TGM2 inhibitors as potential neurodegenerative therapy
DURHAM, N.C.—In tests with fruit flies, a Duke University Medical Center research team has found that orally active transglutaminase inhibitors show promise to prevent or treat Huntington's disease, Alzheimer's disease and other neurodegenerative diseases—as well as perhaps a host of non-neurological conditions.
For the study, Dr. Thung S. Lai, lead author and a Duke associate professor of medicine, carefully and thoroughly screened 2,000 compounds, finding just two groups of drugs were found to be effective at blocking an enzyme called tissue transglutaminase (TGM2). The most potent TGM2 inhibitors in these two groups of drugs were given to the fruit flies along with their food. As a result, the scientists were able to prevent Huntington's disease-like illness in mutant fruit flies and they greatly improved survival in fruit flies that had the same disease process found in Huntington's disease.
To date, there are few reports of anyone using an orally active TGM2 inhibitor to modify TGM2-based disease process, the team notes. 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.
TGM2 may damage cells by forming strong bonds between proteins, notes Dr. Charles S. Greenberg, a professor of medicine and pathology at Duke University Medical Center and senior author of the paper, Identification of Chemical Inhibitors to Human Tissue Transglutaminase by Screening Existing Drug Libraries, which was published in the Sept. 22 issue of Chemistry and Biology.
"When these proteins activate inside cell that causes problems because you end up with too many insoluble or protease-resistant proteins in the cell, something that may very well be a factor in Huntington's, Parkinson's and Alzheimer's, for example," Greenberg explains. "When that happens outside the cell, the proteins become resistant and it serves as a tissue stabilizing factor and is useful for blood clotting, for example, but when it happens inside the cell, bad things happen."
Lai notes that the finding of the team "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."
In fact, the researchers plan to test whether the TGM2 inhibitors they identified would prevent the fibrous tissue process that causes chronic renal, vascular and lung disease.
Greenberg says that fibrosis related to radiation treatments may also be a candidate for treatment with TGM2 inhibitors.
"You see this same enzyme overproduced with radiation fibrosis, so blocking it in such patients with inhibitors like these could be useful," Greenberg notes. "Also, although we haven't talked about this much outside our team, TGM2 is basically the same enzyme that causes celiac disease, so these inhibitors might have some utility there. The problem is that taking them for celiac disease would be a lifelong process, and I worry that such long-term use of a TGM2 inhibitor might have several unpleasant side effects for such patients."
As the team wrote in the published paper, "To our knowledge, this is the first example of screening existing drug libraries for TGM2 inhibitors and may lead to further advances in development of orally active TGM2 inhibitors. As some older drugs have been found to have new uses, our data are significant in providing important leads to develop more specific inhibitors to TGM2 that can be applied to the devastating neurodegenerative disease mediated by polyQ-expressing proteins. Our findings may also aid in the development of drugs inhibiting TGM2-dependent pathology associated with tissue fibrosis, aging, and organ failure."
While these compounds were promising in the animal system, they are several years away from entering any human trials, Greenberg says.
"We will be studying these compounds in diseases in which TGM2 produces tissue injury," he says.
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.
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.
Other authors on the paper include Yusha Liu, Tim Tucker, James R. Burke and Warren J. Strittmatter of the Duke Department of Medicine; Kurt R. Daniel and David C. Sane of the Department of Internal Medicine-Cardiology, Wake Forest University School of Medicine in Winston-Salem, N.C.; and Eric Toone of the Duke Department of Chemistry. DDN