The long-term goal of this research is to develop orally active insulin mimetic drugs based on novel paradigms for the development of small molecule ligands for growth factor receptors. This goal will be accomplished by synthesis of natural product libraries using combinatorial chemistry and their screening against receptor tyrosine kinases, It will be aided by the identification of cytoplasmic proteins that bind to the novel insulin mimetic natural product demethylasterriquinone B1 (DAQ B1), and by direct examination of the interactions of DAQ B 1 with the insulin receptor cytoplasmic domain. The ultimate outcome of this research would be elimination of the need for insulin injections. This project will utilize the following methods: organic synthesis, medicinal and combinatorial chemistry, phage display cloning, and protein chemistry. Assays of the products will include in vitro and in cyto insulin receptor activation, and study of their cytotoxic and cellular transport properties. This research will be significant because substances that can elicit the same biological response as insulin but that are not proteins, and therefore may be orally active, would be of significant value in diabetes management. They would eliminate the need for hypodermic syringes/needles, obviating concerns about contamination and increasing the convenience of administration, with a likely enhancement in patient compliance. They would therefore increase the reliability of diabetes management, particularly for children.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060532-04
Application #
7111733
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Sechi, Salvatore
Project Start
2003-07-15
Project End
2007-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
4
Fiscal Year
2006
Total Cost
$217,821
Indirect Cost
Name
University of California Riverside
Department
Chemistry
Type
Schools of Earth Sciences/Natur
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521
Xiong, Xin; Pirrung, Michael C (2008) Modular synthesis of candidate indole-based insulin mimics by Claisen rearrangement. Org Lett 10:1151-4
Pirrung, Michael C; Deng, Liu; Lin, Bo et al. (2008) Quinone replacements for small molecule insulin mimics. Chembiochem 9:360-2
Xiong, Xin; Pirrung, Michael C (2007) Practical synthesis of 7-prenylindole. J Org Chem 72:5832-4
Kim, Hyunsoo; Deng, Liu; Xiong, Xin et al. (2007) Glyceraldehyde 3-phosphate dehydrogenase is a cellular target of the insulin mimic demethylasterriquinone B1. J Med Chem 50:3423-6
Pirrung, Michael C; Li, Zhitao; Hensley, Erika et al. (2007) Parallel synthesis of indolylquinones and their cell-based insulin mimicry. J Comb Chem 9:844-54
Pirrung, Michael C; Liu, Yufa; Deng, Liu et al. (2005) Methyl scanning: total synthesis of demethylasterriquinone B1 and derivatives for identification of sites of interaction with and isolation of its receptor(s). J Am Chem Soc 127:4609-24