COLLABORATIONS BETWEEN CHEMISTS AND BIOLOGISTS - Collaborative Computational Technologies for Biomedical Research - page 118

the major grant for my group to pursue the highest risk research in peptide
and peptidomimetic science which would be applicable to biological prob-
lems. Its major goals evolved around the design of novel constrained peptide
and peptidomimetic structures, new structural templates, and the asymmetric
synthesis of novel amino acids and other “templates” which could be used to
explore the importance of chi space in peptide and protein structural and
biological function [4, 5]. In other words, its goal was to make synthetic and
structural organic chemistry compatible with the chemistry of peptides, pro-
teins, and other biological compounds. These novel structures and synthetic
methods were designed for applications to the peptide hormones and neu-
rotransmitters we were investigating with our biological collaborators. As
would be expected, these novel templates and structures failed from time to
time, but they also led to numerous successful innovations and novel biologi-
cal functions and were beginning to provide new and useful insight into what
kind of structural constraints in phi/psi space and also in chi space could lead
to structures with unique biology. However, just as this grant got the best
reviews of my career from the NSF, the NSF decided not to continue to
support this research. Though I protested and asked for a rationale for why
it would no longer support my research in this area of ligand design and its
relationship to biological function, I never received an explanation. Much of
what I proposed still awaits effort to determine its potential in peptide and
peptide mimetic design and synthesis.
A similar fate occurred several years later in a grant that I had for over 20
years from the National Institutes of Heath (NIH) in diabetes research and
the involvement of glucagon in diabetes among its goals. We were the fi rst to
design and prepare a glucagon receptor antagonist and to demonstrate with
our collaborator David Johnson that it lowers blood glucose levels in diabetic
animals [6]. However, it also had partial agonist activity, and in other animal
models it was not as effective. We continued to develop more potent glucagon
receptor antagonist and using these and other glucagon analogues were able
to demonstrate with Miles Houslay that glucagon stimulates more than one
signaling pathway, which at that time was a revolutionary discovery [7], that
is that signaling through G-protein coupled receptors (GPCRs) could be medi-
ated by multiple signaling pathway [cyclic adenosine monophosphate (cAMP)
Ca 2+ , phosphoinositol, etc.]. As a result of these and other novel discoveries
we were awarded an NIH MERIT Award. However, obtaining a highly effi ca-
cious glucagon antagonist that could be used for treating diabetics proved
elusive in our research group and in others in academia and industry. Using a
highly sensitive assay, we had found that these potent in vitro antagonists had
weak agonist activity in vivo, which signifi cantly reduced their effi cacy in reduc-
ing glucose levels in most animal diabetic models. Eventually we obtained pure
glucagon antagonists/inverse agonists, but just as we were testing the effi cacy
of one of these analogues in animal models (dogs and rats), our NIH support
was terminated. The possible utilization of pure glucagon receptor antagonists
and inverse agonists in the treatment of diabetes remains to be determined.