Biomedical Engineering Reference
In-Depth Information
The therapeutic interest of inhibiting glucagon signalling for the treatment of
diabetes and obesity (Bagger et al.
2011
; Unger and Cherrington
2012
) has led to
extensive research of competitive antagonists of the glucagon receptor (Cho et al.
2012
). Many peptide antagonists have been described, most of which are analogues
of glucagon, modified at positions critical for binding or activation of the recep-
tor, such as [1-N α-trinitrophenyl histidine, 12-homoarginine]-glucagon (Bregman
et al.
1980
; Johnson et al.
1982
) and des-His1-[Nle9-Ala11-Ala16]-glucagon amide
(Unson et al.
1994a
; Fig.
3.3b
). In addition, chimeric peptides have been designed
to generate molecules capable of modulating both the receptors of glucagon and
GLP-1 (Pan et al.
2006
; Claus et al.
2007
). Since the first report of a non-peptide
agonist in 1998 (Madsen et al.
1998
), small molecule antagonists have arisen a high
interest and several have been validated in preclinical models of type-2 diabetes
(Shen et al.
2011
). These compounds exhibit a variety of structural motifs that are
reviewed in two recent review articles (Shen et al.
2011
; Cho et al.
2012
).
Potterat et al. (2004) reported that BI-32169 (Fig.
3.3c
) exhibits a strong inhibito-
ry activity against glucagon-induced cAMP elevation, with an IC
50
value of 440 nM
(Potterat et al.
2004
). Its C-terminal methyl ester derivative also displayed antago-
nist activity (IC
50
320 nM). The inhibitory activity of BI-32169 and its derivative
was assessed in a BHK-21 cell line stably transfected with a plasmid construct cod-
ing for the human glucagon receptor. Both compounds were found to be selective
for the human glucagon antagonist versus the human GLP-1 receptor. BI-32169 is
the first antagonist of peptidic nature having a sequence that is not derived from glu-
cagon. Glucagon and BI-32169 are very different in terms of primary and secondary
structures, and thus the mechanisms involved in the antagonist properties of BI-
32169 are not understood and have not been investigated until now. Since peptide
antagonists of the glucagon receptor appear less attractive than small molecules for
therapeutic applications, due to a general lower stability, the lasso topology and its
particular structural properties (see Chap. 2) could provide an attractive scaffold to
develop new peptide antagonists with enhanced stability. Therefore, analyzing the
pharmacokinetic and pharmacodynamic properties of BI-32169 together with its
structure/activity relationships is of high interest for receptor antagonist drug design.
3.1.2
Enzyme Inhibitors
The lasso peptide MS-271 (formerly known as siamycin I; Tsunakawa et al.,
1995
),
produced by
Streptomyces
sp., is an inhibitor of smooth muscle myosin light chain
kinase (MLCK; Yano et al.
1996
). MLCK is a Ca
2+
/calmodulin-dependent kinase,
distributed in higher vertebrates. In human, different isoforms derived from three
different genes and resulting from alternative splicing or alternative initiation sites
have been reported. These isoforms are named according to their pattern of ex-
pression. The skeletal and cardiac isoforms, mainly expressed in the skeletal and
cardiac muscle, respectively, derive each from a single gene (
mylk
2 and
mylk
3, re-
spectively). The smooth muscle isoform (or short isoform) and non-muscle isoform
Search WWH ::
Custom Search