GLUCAGON STRUCTURE FUNCTION STUDIES

The primary aim of this research is to obtain an understanding of the
chemical-physical basis for glucagon structure-biological activity
relationships with the goal of developing glucagon analogues and
derivatives which can act as specific inhibitors (antagonists) of glucagon
action. We will then utilize these glucagon antagonists to obtain a deeper
understanding of the role of glucagon in the normal state and in diabetes
mellitus. An ultimate goal of this research is the design, synthesis, and
development of an orally active glucagon antagonist for use in the
treatment of diabetes mellitus. Recently we have developed a number of
glucagon inhibitors (antagonists), and have demonstrated that the most
active one can dramatically lower blood glucose levels in diabetic
animals. We propose to follow up on the structural, synthetic, chemical,
and biological insights we have gained from these studies in several ways:
1) we will further examine the in vivo and in vitro biological activities
of our glucagon antagonists; 2) develop further synthetic and semisynthetic
methods to obtain more potent, longer acting glucagon antagonist analogues
(including fragment analogues); 3) carefully examine conformational and
dynamic properties of the glucagon agonist and antagonist analogues and
structure-biological activity relationships of these analogues in several
assay systems, and then utilize this data to design (and synthesize) more
potent antagonists; 4) develop better analytical and preparative
purification methods, especially high pressure liquid chromatography, for
glucagon and its analogues and derivatives so that the purest possible
synthetic and semisynthetic analogues can be obtained; 5) examine the
properties of glucagon receptors including the effects of ions and
co-factors on glucagon agonist and antagonist binding; and 6) continue
collaborations on the potential use of glucagon antagonists for the
treatment of diabetes.