Novel O-GLcNAcase Inhibitor and Fluorogenic Substrate as a Tool for Diagnosing Type 2 Diabetes
Posted Nov 24 2009 4:00pm
Description of Invention: NIH researchers have synthesized a novel analogue of O-(2-acet-amido-2-deoxy-D-glycopyrano-sylidene)amino-N-phenylcarbamate (PUGNAc), which bears an extension on the N-acetyl moiety. This modified PUGNAc acts as a selective inhibitor of O-GlcNAcase; an enzyme that removes N-acetylglucosamine from nuclear and cytoplasmic proteins, and whose inhibition is associated with the development of Type 2 diabetes. The most desirable feature of this new compound is its ability to specifically inhibit O-GlcNAcase without targeting the related hexosaminidase A (HEX A) and hexoaminidase B (HEX B) enzymes. This unique property distinguishes it from the original PUGNAc and other compounds which inhibit O-GlcNAcase as well as other enzymes. It also has a smaller inhibitory effect on O-GlcNAcase compared to the original PUGNAc. These properties make the modified PUGNAc useful for diagnostic or therapeutic applications involving Type 2 diabetes.
A fluorescent derivative of the modified PUGNAc has also been developed. Modified PUGNAc, conjugated to a fluorescent moiety such as 4-methylumbelliferone, can serve as a substrate for O-GlcNAcase without inhibiting HEX A. This allows the fluorescently labeled compound to be used for measuring O-GlcNAcase enzyme activity, and thus provide a means of diagnosing Type 2 diabetes in human blood or tissue samples. Previous reagents have monitored other Type 2 diabetes related enzymes, but with much less specificity. Recent studies that link mutations of the MGEA5 gene (which codes for O-GlcNAcase) to Type 2 diabetes provide further support for the use of the fluorescent derivative as a potent tool for diagnosing the disease. The fluorogenic derivative may also be used as a novel imaging agent for assessing O-GlcNAcase function in-vivo.
Eun Ju Kim, Melissa Perreira, Craig J. Thomas, and John A. Hanover. An O-GlcNAcase-specific inhibitor and substrate engineered by the extension of the N-acetyl moiety. J Am Chem Soc. 2006 Apr 5;128(13):4234-4235. [ PubMed abs ]
Licensing Status: Available for licensing.
Collaborative Research Opportunity: The NIDDK Laboratory of Cell Biochemistry and Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize modified PUGNAc for prevention or treatment of Type 2 diabetes. Please contact Cindy K. Fuchs, J.D. at 301-451-3636 or email@example.com for more information.
Portfolios: Internal Medicine Internal Medicine - Diagnostics Internal Medicine - Therapeutics
For Additional Information Please Contact: Suryanarayana Vepa Ph.D. NIH Office of Technology Transfer 6011 Executive Blvd. Suite 325, Rockville, MD 20852 United States Email: firstname.lastname@example.org Phone: 301-435-5020 Fax: 301-402-0220