Abstract
The alarming increase in the prevalence of obesity and associated comorbidities
such as type 2 diabetes emphasizes the urgent need for new drugs with
both anorectic and antidiabetic eects. Several peptide hormones secreted
from the gastrointestinal tract play an important role in the physiological
regulation of appetite, food intake, and glucose homeostasis, and many
of these peptides display a signicant potential for treatment of obesity
and/or type 2 diabetes. This Ph.D. thesis describes three novel approaches
for utilizing gut peptides as the starting point for developing obesity and
diabetes drugs.
Project I concerned the design and synthesis of lipidated analogs of
neuromedin U (NMU). The lipidated NMU analogs displayed in vitro potencies
in the nanomolar range for both NMU receptor 1 and NMU receptor
2. Acute treatment of lean mice with the lipidated NMU analogs caused a
dose-dependent reduction of food intake, which was enhanced compared to
native NMU.
Project II explored the design, synthesis, and characterization of neoglycolipidated
analogs of glucagon-like peptide 1 (GLP-1). Neoglycolipidation
reduced lipophilicity and maintained or even improved in vitro potency
towards the GLP-1 receptor. In addition, neoglycolipidation led to selfassembly
and formation of well-dened oligomers as well as non-covalent
binding to human serum albumin. In lean mice, acute treatment of lean
mice with the neoglycolipidated GLP-1 analogs provided a marked improvement
of glucose homeostasis and a potent inhibition of food intake. Taken
together, these data emphasize the potential of neoglycolipidation as a novel
method for modulating the therapeutic properties of peptides.
Project III focused on the design and synthesis of peptides with combined
secretin (Sct) and GLP-1 activity. By merging the pharmacophores of
Sct and GLP-1 into one linear peptide sequence, we obtained a lead candidate,
named GUB06-046, with in vitro potency in the low nanomolar range
for both the Sct receptor and the GLP-1 receptor. Chronic treatment of
db/db mice with GUB06-046 reduced food intake and improved glycaemic
control. Subsequent stereological analyses of the pancreata showed that
chronic treatment with GUB06-046 led to increased cell mass in db/db
mice.
The results of projects I and II clearly illustrate how chemical modications
can improve the pharmacological properties of native peptides. Collectively,
the ndings of this thesis contribute to emphasize the tremendous
therapeutic potential of gut peptides for treatment of obesity and diabetes.
such as type 2 diabetes emphasizes the urgent need for new drugs with
both anorectic and antidiabetic eects. Several peptide hormones secreted
from the gastrointestinal tract play an important role in the physiological
regulation of appetite, food intake, and glucose homeostasis, and many
of these peptides display a signicant potential for treatment of obesity
and/or type 2 diabetes. This Ph.D. thesis describes three novel approaches
for utilizing gut peptides as the starting point for developing obesity and
diabetes drugs.
Project I concerned the design and synthesis of lipidated analogs of
neuromedin U (NMU). The lipidated NMU analogs displayed in vitro potencies
in the nanomolar range for both NMU receptor 1 and NMU receptor
2. Acute treatment of lean mice with the lipidated NMU analogs caused a
dose-dependent reduction of food intake, which was enhanced compared to
native NMU.
Project II explored the design, synthesis, and characterization of neoglycolipidated
analogs of glucagon-like peptide 1 (GLP-1). Neoglycolipidation
reduced lipophilicity and maintained or even improved in vitro potency
towards the GLP-1 receptor. In addition, neoglycolipidation led to selfassembly
and formation of well-dened oligomers as well as non-covalent
binding to human serum albumin. In lean mice, acute treatment of lean
mice with the neoglycolipidated GLP-1 analogs provided a marked improvement
of glucose homeostasis and a potent inhibition of food intake. Taken
together, these data emphasize the potential of neoglycolipidation as a novel
method for modulating the therapeutic properties of peptides.
Project III focused on the design and synthesis of peptides with combined
secretin (Sct) and GLP-1 activity. By merging the pharmacophores of
Sct and GLP-1 into one linear peptide sequence, we obtained a lead candidate,
named GUB06-046, with in vitro potency in the low nanomolar range
for both the Sct receptor and the GLP-1 receptor. Chronic treatment of
db/db mice with GUB06-046 reduced food intake and improved glycaemic
control. Subsequent stereological analyses of the pancreata showed that
chronic treatment with GUB06-046 led to increased cell mass in db/db
mice.
The results of projects I and II clearly illustrate how chemical modications
can improve the pharmacological properties of native peptides. Collectively,
the ndings of this thesis contribute to emphasize the tremendous
therapeutic potential of gut peptides for treatment of obesity and diabetes.
| Original language | English |
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| Publisher | Department of Chemistry, Faculty of Science, University of Copenhagen |
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| Publication status | Published - 2016 |