Optimal control of Type I diabetes mellitus (DM) often requires a combination of rapid- acting and long-acting insulin analogs to achieve tight glycemic control. Current rapid- acting analogs, a pioneering triumph of biotechnology 15 years ago, are nonetheless too delayed in absorption for either ideal meal-time glycemic control or the safe and effective use of automated insulin pumps. We therefore seek to develop a second-generation rapid-acting insulin analog with substantially improved properties in order to provide additional benefits to patients. To this end, we first propose to optimize and apply a novel total chemical synthesis of insulin that provides for highly efficient folding/formation of disulfides. Facile chemical synthesis of insulin will enable the incorporation of a wide range of non-coded amino acids in order to systematically tune the properties of the insulin molecule. We will prepare a series of designed chemical analogs of insulin for biophysical characterization, receptor binding assays, and biological testing in animal models of DM. Our design goals for a second-generation insulin analog include: (i) faster onset of action;(ii) briefer duration of action;(iii) enhanced physical stability;(iv) enhanced chemical stability;and (v) enhanced receptor selectivity. Our proposed research promises to expand the chemical space of insulin therapeutics to exploit for the first time the armamentarium of modern medicinal chemistry.

Public Health Relevance

Our goal is to develop a second-generation rapid-acting insulin analog with substantially improved properties in order to provide additional benefits to patients. We will prepare a series of designed chemical analogs of insulin for biophysical characterization, receptor binding assays, and biological testing in animal models of diabetes mellitus. Our proposed research promises to expand the chemical space of insulin therapeutics to exploit for the first time the armamentarium of modern medicinal chemistry.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK089934-04
Application #
8473857
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (03))
Program Officer
Pawlyk, Aaron
Project Start
2010-08-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$355,263
Indirect Cost
$66,707
Name
University of Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637