NZ748012B2 - Novel oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same - Google Patents
Novel oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same Download PDFInfo
- Publication number
- NZ748012B2 NZ748012B2 NZ748012A NZ74801212A NZ748012B2 NZ 748012 B2 NZ748012 B2 NZ 748012B2 NZ 748012 A NZ748012 A NZ 748012A NZ 74801212 A NZ74801212 A NZ 74801212A NZ 748012 B2 NZ748012 B2 NZ 748012B2
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- New Zealand
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- seq
- oxyntomodulin
- peptide
- obesity
- glp
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Abstract
peptide comprising SEQ ID NO: 4 (HGQGTFTSDYSRYLEEEAVRLFIEWLKNGGPSSGAPPPS) or SEQ ID NO: 5 (HGQGTFTSDYSRQMEEEAVRLFIEWLKNGGPSSGAPPPS) for the manufacture of a medicament for the prevention or treatment of obesity in a subject at risk of obesity or having obesity.
Description
DESCRIPTION
Invention Title: Novel oxyntomodulin derivatives and Pharmaceutical Composition for
treating obesity comprising the same
Related Applications
This is a divisional of New Zealand Patent Application No. 734808, which is a
divisional of New Zealand Patent Application No. 731342, which is a divisional of New Zealand
Patent Application No. 727090, which is a divisional of New Zealand Patent Application No.
717174, which is a divisional of New Zealand Patent Application No. 618810, which is the
Australian National Phase of filed on 7 June 2012, which claims priority
from KR 100056472 filed on 10 June 2011. The entire contents of each application listed
in this paragraph are incorporated herein by reference.
Technical Field
The present invention relates to a novel peptide showing excellent activities on a
glucagon like peptide-1 receptor and a glucagon receptor greater than native
oxyntomodulin, and a composition for the prevention or treatment of obesity comprising
the peptide as an active ingredient.
Background Art
Recently, economic growth and changes in lifestyle are leading to changes in eating
habits. The main causes of rising overweight and obesity rates in contemporary people
are consumption of high-calorie foods such as fast foods and lack of exercise. World
Health Organization (WHO) estimates that more than 1 billion people worldwide are
overweight and at least 300 million of them are clinically obese. In particular, 250,000
people die each year in Europe and more than 2.5 million people worldwide die each year
as a result of being overweight (World Health Organization, Global Strategy on Diet,
Physical Activity and Health, 2004).
Being overweight and obese increases blood pressure and cholesterol levels to cause
occurrence or exacerbation of various diseases such as cardiovascular disease, diabetes,
and arthritis, and are also main causes of rising incidence rates of arteriosclerosis,
hypertension, hyperlipidemia or cardiovascular disease in children or adolescents as well
as in adults.
Obesity is a severe condition that causes various diseases worldwide. It is thought to be
overcome by individual efforts, and it is also believed that obese patients lack self-control.
However, it is difficult to treat obesity, because obesity is a complex disorder involving
appetite regulation and energy metabolism. For the treatment of obesity, abnormal
actions associated with appetite regulation and energy metabolism should be treated
together with efforts of obese patients. Many attempts have been made to develop drugs
capable of treating the abnormal actions. As the result of these efforts, drugs such as
Rimonabant (Sanofi-Aventis), Sibutramin (Abbott), Contrave (Takeda), and Orlistat
(Roche) have been developed, but they have the disadvantages of serious adverse effects
or very weak anti-obesity effects. For example, it was reported that Rimonabant
(Sanofi-Aventis) shows a side-effect of central nerve disorder, Sibutramine (Abbott) and
Contrave (Takeda) show cardiovascular side-effects, and Orlistat (Roche) shows only 4
kg of weight loss when taken for 1 year. Unfortunately, there are no therapeutic agents
for obesity which can be safely prescribed for obese patients.
Many studies have been made to develop therapeutic agents for obesity which do not
have the problems of the conventional anti-obesity drugs. Recently, glucagon
derivatives have received much attention. Glucagon is produced by the pancreas when
the level of glucose in the blood drops resulting from other medications or diseases,
hormone or enzyme deficiencies. Glucagon stimulates glycogen breakdown in the liver,
and facilitates glucose release to raise blood glucose levels to a normal range. In
addition to the effect of increasing the blood glucose level, glucagon suppresses appetite
and activates hormone-sensitive lipase(HSL) of adipocytes to facilitate lipolysis, thereby
showing anti-obesity effects. One of the glucagon derivatives, glucagon like peptide-1
(GLP-1) is under development as a therapeutic agent for hyperglycemia in patients with
diabetes, and it functions to stimulate insulin synthesis and secretion, to inhibit glucagon
secretion, to slow gastric emptying, to increase glucose utilization, and to inhibit food
intake. Exendin-4 is isolated from lizard venom that shares approximately 50% amino
acid homology with GLP-1 and is also reported to activate the GLP-1 receptor, thereby
ameliorating hyperglycemia in patients with diabetes. However, anti-obesity drugs
including GLP-1 are reported to show side-effects such as vomiting and nausea.
As an alternative to GLP-1, therefore, much attention has been focused on
oxyntomodulin, a peptide derived from a glucagon precursor, pre-glucagon that binds to
the receptors of two peptides, GLP-1 and glucagon. Oxyntomodulin represents a potent
anti-obesity therapy, because it inhibits food intake like GLP-1, promotes satiety, and has
a lipolytic activity like glucagon.
Based on the dual function of the oxyntomodulin peptide, it has been actively studied as a
drug for the treatment of obesity. For example, Korean Patent No. 925017 discloses a
pharmaceutical composition including oxyntomodulin as an active ingredient for the
treatment of overweight human, which is administered via an oral, parenteral, mucosal,
rectal, subcutaneous, or transdermal route. However, it has been reported that this
anti-obesity drug including oxyntomodulin has a short in vivo half-life and weak
therapeutic efficacy, even though administered at a high dose three times a day. Thus,
many efforts have been made to improve the in vivo half-life or therapeutic effect of
oxyntomodulin on obesity by its modification.
For example, a dual agonist oxyntomodulin (Merck) is prepared by substituting L-serine
with D-serine at position 2 of oxyntomodulin to increase a resistance to dipeptidyl
peptidase-IV (DPP-IV) and by attaching a cholesterol moiety at the C-terminal to
increase the blood half-life at the same time. ZP2929 (Zealand) is prepared by
substituting L-serine with D-serine at position 2 to enhance resistance to DPP-IV,
substituting arginine with alanine at position 17 to enhance resistance to protease,
substituting methionine with lysine at position 27 to enhance oxidative stability, and
substituting glutamine with aspartic acid and alanine at positions 20 and 24 and
asparagine with serine at position 28 to enhance deamidation stability. However, even
though the half-life of the dual agonist oxyntomodulin (Merck) was enhanced to show
half-life 8~12 minutes longer than the native oxyntomodulin, it still has a very short in
vivo half-life of 1.7 hr and its administration dose is also as high as several mg/kg.
Unfortunately, oxyntomodulin or derivatives thereof have disadvantages of daily
administration of high dose due to the short half-life and low efficacy.
Disclosure
Technical Problems
Accordingly, the present inventors have developed an oxyntomodulin derivative prepared
by modifying the amino acid sequence of native oxyntomodulin in order to enhance its
therapeutic effects on obesity and to reduce its administration dose. As a result, they
found that the oxyntomodulin derivative shows more excellent activities on a glucagon
receptor and a GLP-1 receptor than native oxyntomodulin, thereby completing the
present invention.
Technical Solution
An object of the present invention is to provide a novel peptide showing excellent
therapeutic effects on obesity.
Another object of the present invention is to provide a composition for the prevention or
treatment of obesity, comprising the peptide.
Still another object of the present invention is to provide a method for preventing or
treating obesity by administering the peptide or the composition to a subject.
Still another object of the present invention is to provide use of the peptide in the
preparation of drugs for the prevention or treatment of obesity.
Advantageous Effects
Unlike native oxyntomodulin, the novel peptide of the present invention reduces food
intake, suppresses gastric emptying, and facilitates lipolysis without side-effects, and also
shows excellent receptor-activating effects. Thus, it can be widely used in the treatment
of obesity with safety and efficacy.
Description of Drawings
is a graph showing changes in food intake according to administration dose of
oxyntomodulin or oxyntomodulin derivative.
Best Mode for Carrying out the Invention
In one aspect to achieve the above objects, the present invention provides a novel peptide
including the amino acid sequence of the following Formula 1.
R1-X1-X2-GTFTSD-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X1
8-X19-X20-X21-X22-X23-X24-R2 (SEQ ID NO: 51) (Formula 1)
wherein R1 is histidine, desamino-histidyl, dimethyl-histidyl (N-dimethyl-histidyl),
beta-hydroxyimidazopropionyl, 4-imidazoacetyl, beta-carboxy imidazopropionyl or
tyrosine;
X1 is Aib(aminoisobutyric acid), d-alanine, glycine, Sar(N-methylglycine), serine, or
d-serine;
X2 is glutamic acid or glutamine;
X3 is leucine or tyrosine;
X4 is serine or alanine;
X5 is lysine or arginine;
X6 is glutamine or tyrosine;
X7 is leucine or methionine;
X8 is aspartic acid or glutamic acid;
X9 is glutamic acid, serine, alpha-methyl-glutamic acid or is deleted;
X10 is glutamine, glutamic acid, lysine, arginine, serine or is deleted;
X11 is alanine, arginine, valine or is deleted;
X12 is alanine, arginine, serine, valine or is deleted;
X13 is lysine, glutamine, arginine, alpha-methyl-glutamic acid or is deleted;
X14 is aspartic acid, glutamic acid, leucine or is deleted;
X15 is phenylalanine or is deleted;
X16 is isoleucine, valine or is deleted;
X17 is alanine, cysteine, glutamic acid, lysine, glutamine, alpha-methyl-glutamic acid or
is deleted;
X18 is tryptophan or is deleted;
X19 is alanine, isoleucine, leucine, serine, valine or is deleted;
X20 is alanine, lysine, methionine, glutamine, arginine or is deleted;
X21 is asparagine or is deleted;
X22 is alanine, glycine, threonine or is deleted;
X23 is cysteine, lysine or is deleted;
X24 is a peptide having 2 to 10 amino acids consisting of combinations of alanine,
glycine and serine, or is deleted; and
R2 is KRNRNNIA (SEQ ID NO. 32), GPSSGAPPPS (SEQ ID NO. 33),
GPSSGAPPPSK (SEQ ID NO. 34), HSQGTFTSDYSKYLD (SEQ ID NO. 35),
HSQGTFTSDYSRYLDK (SEQ ID NO. 36), HGEGTFTSDLSKQMEEEAVK (SEQ ID
NO. 37) or is deleted (excluded if the amino acid sequence of Formula 1 is identical to
that of SEQ ID NO. 1).
As used herein, the term "peptide" means a compound of two or more α-amino acids
linked by a peptide bond. With respect to the objects of the present invention, it means
a peptide that activates both the GLP-1 receptor and the glucagon receptor to show
anti-obesity effects. The peptide according to the present invention includes peptides,
peptide derivatives or peptide mimetics that are prepared by addition, deletion or
substitution of amino acids of oxyntomodulin so as to activate both of the GLP-1 receptor
and the glucagon receptor at a high level, compared to the native oxyntomodulin.
Amino acids mentioned herein are abbreviated according to the nomenclature rule of
IUPAC-IUB as follows:
Alanine A Arginine R
Asparagine N Aspartic acid D
Cysteine C Glutamic acid E
Glutamine Q Glycine G
Histidine H Isoleucine I
Leucine L Lysine K
Methionine M Phenylalanine F
Proline P Serine S
Threonine T Tryptophan W
Tyrosine Y Valine V
In the present invention, the peptide encompasses any peptide that is prepared by
substitutions, additions, deletions or post translational modifications (e.g., methylation,
acylation, ubiquitination, intramolecular covalent bonding) in the amino acid sequence of
oxyntomodulin (HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA, SEQ ID
NO. 1) so as to activate the glucagon and GLP-1 receptors at the same time. Upon
substitution or addition of amino acids, any of the 20 amino acids commonly found in
human proteins, as well as atypical or non-naturally occurring amino acids can be used.
Commercially available sources of atypical amino acids include Sigma-Aldrich,
ChemPep Inc., and Genzyme Pharmaceuticals. The peptides including these amino
acids and atypical peptide sequences may be synthesized and purchased from commercial
suppliers, for example, American Peptide Company or Bachem (USA) or Anygen
(Korea).
In order to enhance the activity of the wild-type oxyntomodulin for the glucagon receptor
and the GLP-1 receptor, the peptide of the present invention may be substituted with
4-imidazoacetyl where the alpha carbon of histidine at position 1 of amino acid sequence
represented by SEQ ID NO. 1 is deleted, desamino-histidyl where the N-terminal amino
group is deleted, dimethyl-histidyl (N-dimethyl-histidyl) where the N-terminal amino
group is modified with two methyl groups, beta-hydroxy imidazopropionyl where the
N-terminal amino group is substituted with a hydroxyl group, or beta-carboxy
imidazopropionyl where the N-terminal amino group is substituted with a carboxyl group.
In addition, the GLP-1 receptor-binding region may be substituted with amino acids that
enhance hydrophobic and ionic bonds or combinations thereof. A part of the
oxyntomodulin sequence may be substituted with the amino acid sequence of GLP-1 or
Exendin-4 to enhance the activity on GLP-1 receptor.
Further, a part of the oxyntomodulin sequence may be substituted with a sequence
stabilizing alpha helix. Preferably, amino acids at positions 10, 14, 16, 20, 24 and 28 of
the amino acid sequence of Formula 1 may be substituted with amino acids or amino acid
derivatives consisting of Tyr(4-Me), Phe, Phe(4-Me), Phe(4-Cl), Phe(4-CN), Phe(4-NO ),
Phe(4-NH ), Phg, Pal, Nal, Ala(2-thienyl) and Ala(benzothienyl) that are known to
stabilize alpha helix, and there are no limitations on the type and number of alpha
helix-stabilizing amino acid or amino acid derivatives to be inserted. Preferably, amino
acids at positions 10 and 14, 12 and 16, 16 and 20, 20 and 24, and 24 and 28 may be also
substituted with glutamic acid or lysine, respectively so as to form rings, and there is no
limitation on the number of rings to be inserted. Most preferably, the peptide may be a
peptide having an amino acid sequence selected from the following Formulae 2 to 6.
In one specific embodiment, the peptide of the present invention is an oxyntomodulin
derivative including the amino acid sequence of the following Formula 2 where the
amino acid sequence of oxyntomodulin is substituted with that of exendin or GLP-1.
R1-A-R3 (SEQ UD BI: 52) (Formula 2)
In another specific embodiment, the peptide of the present invention is an oxyntomodulin
derivative including the amino acid sequence of the following Formula 3, which is
prepared by linking a part of the amino acid sequence of oxyntomodulin and a part of the
amino acid sequence of exendin or GLP-1 via a proper amino acid linker.
R1-B-C-R4 (SEQ ID NO: 53) (Formula 3)
In still another specific embodiment, the peptide of the present invention is an
oxyntomodulin derivative including the amino acid sequence of the following Formula 4,
wherein a part of the amino acid sequence of oxyntomodulin is substituted with an amino
acid capable of enhancing the binding affinity to GLP-1 receptor, for example, Leu at
position 26 which binds with GLP-1 receptor by hydrophobic interaction is substituted
with the hydrophobic residue, Ile or Val.
R1-SQGTFTSDYSKYLD-D1-D2-D3-D4-D5-LFVQW-D6-D7-N-D8-R3 (SEQ ID NO:
54) (Formula 4)
In still another specific embodiment, the peptide of the present invention is an
oxyntomodulin derivative including the following Formula 5, wherein a part of the amino
acid sequence is deleted, added, or substituted with other amino acid in order to enhance
the activities of native oxyntomodulin on GLP-1 receptor and glucagon receptor.
R1-E1-QGTFTSDYSKYLD-E2-E3-RA-E4-E5-FV-E6-WLMNT-E7-R5 (SEQ ID NO:
55) (Formula 5)
In Formulae 2 to 5, R1 is the same as in the description of Formula 1;
A is selected from the group consisting of SQGTFTSDYSKYLDSRRAQDFVQWLMNT
(SEQ ID NO. 38), SQGTFTSDYSKYLDEEAVRLFIEWLMNT (SEQ ID NO. 39),
SQGTFTSDYSKYLDERRAQDFVAWLKNT (SEQ ID NO. 40),
GQGTFTSDYSRYLEEEAVRLFIEWLKNG (SEQ ID NO. 41),
GQGTFTSDYSRQMEEEAVRLFIEWLKNG (SEQ ID NO. 42),
GEGTFTSDLSRQMEEEAVRLFIEWAA (SEQ ID NO. 43), and
SQGTFTSDYSRQMEEEAVRLFIEWLMNG (SEQ ID NO. 44);
B is selected from the group consisting of SQGTFTSDYSKYLDSRRAQDFVQWLMNT
(SEQ ID NO. 38), SQGTFTSDYSKYLDEEAVRLFIEWLMNT (SEQ ID NO. 39),
SQGTFTSDYSKYLDERRAQDFVAWLKNT (SEQ ID NO. 40),
GQGTFTSDYSRYLEEEAVRLFIEWLKNG (SEQ ID NO. 41),
GQGTFTSDYSRQMEEEAVRLFIEWLKNG (SEQ ID NO. 42),
GEGTFTSDLSRQMEEEAVRLFIEWAA (SEQ ID NO. 43),
SQGTFTSDYSRQMEEEAVRLFIEWLMNG (SEQ ID NO. 44),
GEGTFTSDLSRQMEEEAVRLFIEW (SEQ ID NO. 45), and SQGTFTSDYSRYLD
(SEQ ID NO. 46);
C is a peptide having 2 to 10 amino acids consisting of combinations of alanine, glycine
and serine;
D1 is serine, glutamic acid or arginine;
D2 is arginine, glutamic acid or serine;
D3 is arginine, alanine or valine;
D4 is arginine, valine or serine;
D5 is glutamine, arginine or lysine;
D6 is isoleucine, valine or serine;
D7 is methionine, arginine or glutamine;
D8 is threonine, glycine or alanine;
E1 is serine, Aib, Sar, d-alanine or d-serine;
E2 is serine or glutamic acid;
E3 is arginine or lysine;
E4 is glutamine or lysine;
E5 is aspartic acid or glutamic acid;
E6 is glutamine, cysteine or lysine;
E7 is cysteine, lysine or is deleted;
R3 is KRNRNNIA (SEQ ID NO. 32), GPSSGAPPPS (SEQ ID NO. 33) or
GPSSGAPPPSK (SEQ ID NO. 34);
R4 is HSQGTFTSDYSKYLD (SEQ ID NO. 35), HSQGTFTSDYSRYLDK (SEQ ID NO.
36) or HGEGTFTSDLSKQMEEEAVK (SEQ ID NO. 37); and,
R5 is KRNRNNIA (SEQ ID NO. 32), GPSSGAPPPS (SEQ ID NO. 33), GPSSGAPPPSK
(SEQ ID NO. 34) or is deleted (excluded if the amino acid sequences of Formula 2 to 5
are identical to that of SEQ ID NO. 1).
Preferably, the novel peptide of the present invention may be a peptide of the following
Formula 6.
R1-X1-X2-GTFTSD-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X
18-X19-X20-X21-X22-X23-X24-R2 (SEQ ID NO: 56) (Formula 6)
wherein R1 is histidine, desamino-histidyl, 4-imidazoacetyl or tyrosine;
X1 is Aib(aminoisobutyric acid), glycine or serine;
X2 is glutamic acid or glutamine;
X3 is leucine or tyrosine;
X4 is serine or alanine;
X5 is lysine or arginine;
X6 is glutamine or tyrosine;
X7 is leucine or methionine;
X8 is aspartic acid or glutamic acid;
X9 is glutamic acid, alpha-methyl-glutamic acid or is deleted;
X10 is glutamine, glutamic acid, lysine, arginine or is deleted;
X11 is alanine, arginine or is deleted;
X12 is alanine, valine or is deleted;
X13 is lysine, glutamine, arginine, alpha-methyl-glutamic acid or is deleted;
X14 is aspartic acid, glutamic acid, leucine or is deleted;
X15 is phenylalanine or is deleted;
X16 is isoleucine, valine or is deleted;
X17 is alanine, cysteine, glutamic acid, glutamine, alpha-methyl-glutamic acid or is
deleted;
X18 is tryptophan or is deleted;
X19 is alanine, isoleucine, leucine, valine or is deleted;
X20 is alanine, lysine, methionine, arginine or is deleted;
X21 is asparagine or is deleted;
X22 is threonine or is deleted;
X23 is cysteine, lysine or is deleted;
X24 is a peptide having 2 to 10 amino acids consisting of glycine or is deleted; and
R2 is KRNRNNIA (SEQ ID NO. 32), GPSSGAPPPS (SEQ ID NO. 33), GPSSGAPPPSK
(SEQ ID NO. 34), HSQGTFTSDYSKYLD (SEQ ID NO. 35), HSQGTFTSDYSRYLDK
(SEQ ID NO. 36), HGEGTFTSDLSKQMEEEAVK (SEQ ID NO. 37) or is deleted
(excluded if the amino acid sequence of Formula 6 is identical to that of SEQ ID NO. 1).
More preferably, the peptide of the present invention may be selected from the group
consisting of the peptides of SEQ ID NOs. 1 to 31. Much more preferably, the peptide
of the present invention may be an oxyntomodulin derivative described in Table 1 of
Example 2-1.
Oxyntomodulin has activities of two peptides, GLP-1 and glucagon. GLP-1 decreases
blood glucose, reduces food intake, and suppresses gastric emptying, and glucagon
increases blood glucose, facilitate lipolysis and decreases body-weight by increasing
energy metabolisms. Different biological effects of two peptides can cause undesired
effects like increasing blood glucose if glucagon shows more dominant effect than GLP-1,
or causing nausea and vomiting if GLP-1 shows more dominant effect than glucagon.
Therefore, the oxyntomodulin derivatives of the present invention are not only aimed to
increase these activities, for example, amino acids at position 1 and 11 of oxyntomodulin
which suppress the activity of glucagon, may be modified for balancing the activity ratios
of glucagon and GLP-1.
The present inventors performed in vitro experiments to demonstrate that the peptide of the
present invention shows excellent activities on the GLP-1 receptor and the glucagon
receptor, compared to oxyntomodulin. Thus, it is suggested that the peptide of the
present invention activates the GLP-1 receptor and the glucagon receptor to show more
excellent therapeutic effects on obesity than the conventional oxyntomodulin. In
addition, its inhibitory effects on in vivo food intake were examined, and it shows more
excellent inhibitory effects on food intake than the conventional oxyntomodulin (.
It is apparent to those skilled in the art that when the oxyntomodulin derivatives of the
present invention are modified using the typical techniques, including modification with
polymers such as PEG and sugar chain or fusion with albumin, transferrin, fatty acid, and
immunoglobulin in order to improve the therapeutic effects of the oxyntomodulin
derivatives, they will show superior therapeutic effects to native oxyntomodulin.
Therefore, the modified oxyntomodulin derivatives are also included in the scope of the
present invention.
In another aspect, the present invention provides a polynucleotide encoding the peptide.
The term "homology", as used herein for the polynucleotide, indicates sequence similarity
between wild-type amino acid sequences or wild-type nucleotide sequences, and includes
a gene sequence that is 75% or higher, preferably 85% or higher, more preferably 90% or
higher and even more preferably 95% or higher identical to the polynucleotide sequence
encoding the peptide. The homology evaluation may be done with the naked eye or
using a commercially available program. Using a commercially available computer
program, the homology between two or more sequences may be expressed as a
percentage (%), and the homology (%) between adjacent sequences may be evaluated.
The polynucleotide encoding the peptide is inserted into a vector and expressed so as to
obtain a large amount of the peptide.
In still another aspect, the present invention provides a pharmaceutical composition for the
prevention or treatment of obesity comprising the peptide.
As used herein, the term "prevention" means all of the actions by which the occurrence of
obesity is restrained or retarded by administration of the peptide or the composition, and
the term "treatment" means all of the actions by which the symptoms of obesity have
taken a turn for the better or been modified favorably by administration of the peptide or
the composition.
As used herein, the term "administration" means introduction of an amount of a
predetermined substance into a patient by a certain suitable method. The composition
of the present invention may be administered via any of the common routes, as long as it
is able to reach a desired tissue, for example, but is not limited to, intraperitoneal,
intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal,
intrapulmonary, or intrarectal administration. However, since peptides are digested upon
oral administration, active ingredients of a composition for oral administration should be
coated or formulated for protection against degradation in the stomach.
As used herein, the term "obesity" implies accumulation of an excess amount of adipose
tissue in the body, and a body mass index (body weight (kg) divided by the square of the
height (m)) above 25 is to be regarded as obesity. Obesity is usually caused by an
energy imbalance, when the amount of dietary intake exceeds the amount of energy
expended for a long period of time. Obesity is a metabolic disease that affects the
whole body, and increases the risk for diabetes, hyperlipidemia, sexual dysfunction,
arthritis, and cardiovascular diseases, and in some cases, is associated with incidence of
cancer.
The pharmaceutical composition of the present invention may further include a
pharmaceutically acceptable carrier, excipient, or diluent. As used herein, the term
"pharmaceutically acceptable" means that the composition is sufficient to achieve the
therapeutic effects without deleterious side effects, and may be readily determined
depending on the type of the diseases, the patient's age, body weight, health conditions,
gender, and drug sensitivity, administration route, administration mode, administration
frequency, duration of treatment, drugs used in combination or coincident with the
composition of this invention, and other factors known in medicine.
The pharmaceutical composition including the derivative of the present invention may
further include a pharmaceutically acceptable carrier. For oral administration, the
carrier may include, but is not limited to, a binder, a lubricant, a disintegrant, an excipient,
a solubilizer, a dispersing agent, a stabilizer, a suspending agent, a colorant, and a
flavorant. For injectable preparations, the carrier may include a buffering agent, a
preserving agent, an analgesic, a solubilizer, an isotonic agent, and a stabilizer. For
preparations for topical administration, the carrier may include a base, an excipient, a
lubricant, and a preserving agent.
The composition of the present invention may be formulated into a variety of dosage forms
in combination with the aforementioned pharmaceutically acceptable carriers. For
example, for oral administration, the pharmaceutical composition may be formulated into
tablets, troches, capsules, elixirs, suspensions, syrups or wafers. For injectable
preparations, the pharmaceutical composition may be formulated into an ampule as a
single dosage form or a multidose container. The pharmaceutical composition may also
be formulated into solutions, suspensions, tablets, pills, capsules and long-acting
preparations.
On the other hand, examples of the carrier, the excipient, and the diluent suitable for the
pharmaceutical formulations include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol,
erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium
silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone,
water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and
mineral oils. In addition, the pharmaceutical formulations may further include fillers,
anti-coagulating agents, lubricants, humectants, flavorants, and antiseptics.
Further, the pharmaceutical composition of the present invention may have any formulation
selected from the group consisting of tablets, pills, powders, granules, capsules,
suspensions, liquids for internal use, emulsions, syrups, sterile aqueous solutions,
non-aqueous solvents, lyophilized formulations and suppositories.
Further, the composition may be formulated into a single dosage form suitable for the
patient's body, and preferably is formulated into a preparation useful for peptide drugs
according to the typical method in the pharmaceutical field so as to be administered by an
oral or parenteral route such as through skin, intravenous, intramuscular, intra-arterial,
intramedullary, intramedullary, intraventricular, pulmonary, transdermal, subcutaneous,
intraperitoneal, intranasal, intracolonic, topical, sublingual, vaginal, or rectal
administration, but is not limited thereto.
The peptide may be used by blending with a variety of pharmaceutically acceptable carriers
such as physiological saline or organic solvents. In order to increase the stability or
absorptivity, carbohydrates such as glucose, sucrose or dextrans, antioxidants such as
ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other
stabilizers may be used.
The administration dose and frequency of the pharmaceutical composition of the present
invention are determined by the type of active ingredient, together with various factors
such as the disease to be treated, administration route, patient's age, gender, and body
weight, and disease severity.
The total effective dose of the composition of the present invention may be administered to
a patient in a single dose, or may be administered for a long period of time in multiple
doses according to a fractionated treatment protocol. In the pharmaceutical composition
of the present invention, the content of active ingredient may vary depending on the
disease severity. Preferably, the total daily dose of the peptide of the present invention
may be approximately 0.0001 ㎍ to 500 mg per 1 kg of body weight of a patient.
However, the effective dose of the peptide is determined considering various factors
including patient's age, body weight, health conditions, gender, disease severity, diet, and
secretion rate, in addition to administration route and treatment frequency of the
pharmaceutical composition. In view of this, those skilled in the art may easily
determine an effective dose suitable for the particular use of the pharmaceutical
composition of the present invention. The pharmaceutical composition according to the
present invention is not particularly limited to the formulation, and administration route
and mode, as long as it shows the effects of the present invention.
The pharmaceutical composition of the present invention shows excellent in-vivo duration
of efficacy and titer, thereby remarkably reducing the number and frequency of
administration thereof.
Moreover, the pharmaceutical composition may be administered alone or in combination or
coincident with other pharmaceutical formulations showing prophylactic or therapeutic
effects on obesity. The pharmaceutical formulations showing prophylactic or therapeutic
effects on obesity are not particularly limited, and may include a GLP-1 receptor agonist,
a leptin receptor agonist, a DPP-IV inhibitor, a Y5 receptor antagonist, a
Melanin-concentrating hormone (MCH) receptor antagonist, a Y2/3 receptor agonist, a
MC3/4 receptor agonist, a gastric/pancreatic lipase inhibitor, a 5HT2c agonist, a β3A
receptor agonist, an Amylin receptor agonist, a Ghrelin antagonist, and/or a Ghrelin
receptor antagonist.
In still another aspect, the present invention provides a method for preventing or treating
obesity, comprising the step of administering to a subject the peptide or the
pharmaceutical composition including the same.
In the present invention, the term "subject" is those suspected of having obesity, which
means mammals including human, mouse, and livestock having obesity or having the
possibility of obesity. However, any subject to be treated with the peptide or the
pharmaceutical composition of the present invention is included without limitation. The
pharmaceutical composition including the peptide of the present invention is
administered to a subject suspected of having obesity, thereby treating the subject
effectively. The obesity is as described above.
The therapeutic method of the present invention may include the step of administering the
composition including the peptide at a pharmaceutically effective amount. The total daily
dose should be determined through appropriate medical judgment by a physician, and
administered once or several times. With respect to the objects of the present invention,
the specific therapeutically effective dose level for any particular patient may vary
depending on various factors well known in the medical art, including the kind and
degree of the response to be achieved, concrete compositions according to whether other
agents are used therewith or not, the patient’s age, body weight, health condition, gender,
and diet, the time and route of administration, the secretion rate of the composition, the
time period of therapy, other drugs used in combination or coincident with the
composition of this invention, and like factors well known in the medical arts.
reverse primers including each of the EcoRI and XhoI restriction sites so as to obtain a
PCR product.
Forward primer: 5'-CAGCGACACCGACCGTCCCCCCGTACTTAAGGCC-3'
(SEQ ID NO. 49)
Reverse primer: 5'-CTAACCGACTCTCGGGGAAGACTGAGCTCGCC-3'(SEQ ID NO.
The PCR product was cloned into the known animal cell expression vector x0GC/dhfr to
prepare a recombinant vector x0GC/GCGR.
CHO DG44 cell line cultured in DMEM/F12 (10% FBS) medium was transfected with the
recombinant vector x0GC/GCGR using Lipofectamine, and cultured in a selection
medium containing 1 mg/mL G418 and 10 nM methotraxate. Single clone cell lines
were selected therefrom by a limit dilution technique, and a cell line showing excellent
cAMP response to glucagon in a concentration-dependent manner was finally selected
therefrom.
Example 2. Test on in vitro activity of oxyntomodulin derivatives
Example 2-1: Synthesis of oxyntomodulin derivatives
In order to measure in vitro activities of oxyntomodulin derivatives, oxyntomodulin
derivatives having the following amino acid sequences were synthesized (Table 1).
Table 1
Oxyntomodulin and oxyntomodulin derivatives
SEQ ID NO. Amino acid sequence
SEQ ID NO. 1 HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA
SEQ ID NO. 2 CA-SQGTFTSDYSKYLDEEAVRLFIEWLMNTKRNRNNIA
SEQ ID NO. 3 CA-SQGTFTSDYSKYLDERRAQDFVAWLKNTGPSSGAPPPS
SEQ ID NO. 4 CA-GQGTFTSDYSRYLEEEAVRLFIEWLKNGGPSSGAPPPS
SEQ ID NO. 5 CA-GQGTFTSDYSRQMEEEAVRLFIEWLKNGGPSSGAPPPS
SEQ ID NO. 6 CA-GEGTFTSDLSRQMEEEAVRLFIEWAAHSQGTFTSDYSKYL
SEQ ID NO. 7 CA-SQGTFTSDYSRYLDEEAVRLFIEWLMNTK
SEQ ID NO. 8 CA-SQGTFTSDLSRQLEEEAVRLFIEWLMNK
SEQ ID NO. 9 CA-GQGTFTSDYSRYLDEEAVXLFIEWLMNTKRNRNNIA
SEQ ID NO. 10 CA-SQGTFTSDYSRQMEEEAVRLFIEWLMNGGPSSGAPPPSK
SEQ ID NO. 11 CA-GEGTFTSDLSRQMEEEAVRLFIEWAAHSQGTFTSDYSRYL
SEQ ID NO. 12 CA-SQGTFTSDYSRYLDGGGHGEGTFTSDLSKQMEEEAVK
SEQ ID NO. 13 CA-SQGTFTSDYSRYLDXEAVXLFIEWLMNTK
SEQ ID NO. 14 CA-GQGTFTSDYSRYLDEEAVXLFIXWLMNTKRNRNNIA
SEQ ID NO. 15 CA-GQGTFTSDYSRYLDEEAVRLFIXWLMNTKRNRNNIA
SEQ ID NO. 16 CA-SQGTFTSDLSRQLEGGGHSQGTFTSDLSRQLEK
SEQ ID NO. 17 CA-SQGTFTSDYSRYLDEEAVRLFIEWIRNTKRNRNNIA
SEQ ID NO. 18 CA-SQGTFTSDYSRYLDEEAVRLFIEWIRNGGPSSGAPPPSK
SEQ ID NO. 19 CA-SQGTFTSDYSRYLDEEAVKLFIEWIRNTKRNRNNIA
SEQ ID NO. 20 CA-SQGTFTSDYSRYLDEEAVKLFIEWIRNGGPSSGAPPPSK
SEQ ID NO. 21 CA-SQGTFTSDYSRQLEEEAVRLFIEWVRNTKRNRNNIA
SEQ ID NO. 22 DA-SQGTFTSDYSKYLDEKRAKEFVQWLMNTK
SEQ ID NO. 23 HAibQGTFTSDYSKYLDEKRAKEFVCWLMNT
SEQ ID NO. 24 HAibQGTFTSDYSKYLDEKRAKEFVQWLMNTC
SEQ ID NO. 25 HAibQGTFTSDYSKYLDEKRAKEFVQWLMNTC
SEQ ID NO. 26 HAibQGTFTSDYSKYLDEKRAKEFVQWLMNTC
SEQ ID NO. 27 HAibQGTFTSDYSKYLDEQAAKEFICWLMNT
SEQ ID NO. 28 HAibQGTFTSDYSKYLDEKRAKEFVQWLMNT
SEQ ID NO. 29 CA-AibQGTFTSDYSKYLDEKRAKEFVQWLMNTC
SEQ ID NO. 30 HAibQGTFTSDYAKYLDEKRAKEFVQWLMNTC
SEQ ID NO. 31 YAibQGTFTSDYSKYLDEKRAKEFVQWLMNTC
In Table 1, amino acids in bold and underlined represent ring formation, and amino acids
represented by X mean a non-native amino acid, alpha-methyl-glutamic acid. In
addition, CA represents 4-imidazoacetyl, and DA represents desamino-histidyl.
Example 2-2: Test on in vitro activity of oxyntomodulin derivatives
In order to measure anti-obesity efficacies of the oxyntomodulin derivatives synthesized in
Example 2-1, cell activity was measured in vitro using the cell lines prepared in
Examples 1-1 and 1-2.
The cell lines were those prepared by transfecting CHO (Chinese Hamster Ovary) to
express human GLP-1 receptor gene and glucagon receptor gene, respectively. Thus,
they are suitable to measure GLP-1 and glucagon activities. Therefore, the activity of
each oxyntomodulin derivative was measured using each transformed cell line.
Specifically, each cell line was sub-cultured twice or three time a week, and aliquoted in
each well of a 96-well plate at a density of 1 X 10 , followed by cultivation for 24 hours.
The cultured cells were washed with KRB buffer and suspended in 40 ml of KRB buffer
containing 1 mM IBMX, and left at room temperature for 5 minutes. Oxyntomodulin
(SEQ ID NO. 1) and oxyntomodulin derivatives (represented by SEQ ID NOs. 2-6, 8,
-13, 17, 18, 23-25, 27-30 and 31) were diluted from 1000 nM to 0.02 nM by 5-fold
serial dilution, and each 40 mL thereof was added to the cells, and cultured at 37°C for 1
hour in a CO2 incubator. Then, 20 mL of cell lysis buffer was added for cell lysis, and
the cell lysates were applied to a cAMP assay kit (Molecular Device, USA) to measure
cAMP concentrations. EC values were calculated therefrom, and compared to each
other. EC values are shown in the following Table 2.
Table 2
Table 2
Comparison of in vitro activities for GLP-1 receptor and glucagon receptor between
oxyntomodulin and oxyntomodulin derivatives
SEQ ID NO. EC (nM)
SEQ ID NO. CHO/GLP-1R CHO/GCGR
SEQ ID NO. 1 50 - 210 10 - 43
SEQ ID NO. 2 51.8 12.8
SEQ ID NO. 3 >1,000 637.7
SEQ ID NO. 4 5.5 >1,000
SEQ ID NO. 5 5.9 >1,000
SEQ ID NO. 6 500.1 >1,000
SEQ ID NO. 8 419.6 >1,000
SEQ ID NO. 10 >1,000 >1,000
SEQ ID NO. 11 >1,000 >1,000
SEQ ID NO. 12 >1,000 >1,000
SEQ ID NO. 13 >1,000 >1,000
SEQ ID NO. 17 97.9 >1,000
SEQ ID NO. 18 96.3 >1,000
SEQ ID NO. 23 2.46 5.8
SEQ ID NO. 24 1.43 6.95
SEQ ID NO. 25 1.9 1.3
SEQ ID NO. 27 2.8-5.5 3.1-5.6
SEQ ID NO. 28 3.1 0.3
SEQ ID NO. 29 14.25 17.3
SEQ ID NO. 30 2.20 80.2
SEQ ID NO. 31 12.5 1.0
As shown in Table 2, there were oxyntomodulin derivatives showing excellent in vitro
activities and different ratios of activities on GLP-1 receptor and glucagon receptor,
compared to native oxyntomodulin of SEQ ID NO. 1.
It is known that oxyntomodulin activates both the GLP-1 receptor and glucagon receptor to
suppress appetite, facilitate lipolysis, and promote satiety, thereby showing anti-obesity
effects. The oxyntomodulin derivatives according to the present invention show higher
in vitro activities on both the GLP-1 receptor and glucagon receptor than the wild-type
oxyntomodulin, and therefore can be used as a therapeutic agent for obesity with higher
efficacies than the known oxyntomodulin.
Example 3. Test on in vivo activity of oxyntomodulin derivatives
In order to measure in vivo therapeutic activity of oxyntomodulin derivatives, changes in
food intake by administration of oxyntomodulin derivatives were examined in ob/ob
mouse using native oxyntomodulin as a control.
Specifically, obese diabetic ob/ob mice, commonly used to test the efficacies of therapeutic
agents for obesity and diabetes, were fasted for 16 hours, and administered with 1 or 10
In still another aspect, the present invention provides a use of the peptide or the
pharmaceutical composition including the same in the preparation of drugs for the
prevention or treatment of obesity.
[171A] In still another aspect, the present invention provides a use of the peptide comprising the
amino acid sequence of SEQ ID NO: R or 5.
[171B] In still another aspect, the present invention provides a pharmaceutical composition
comprising the peptide according to the invention as an actie ingredient and a
pharmaceutically acceptable carrier.
[171C] In still another aspect, the present invention provides use of the peptide or the
composition according to the invention in the manufacture of a medicament for the
prevention or treatment of obesity in a subject at risk of obesity or having obesity.
Mode for Invention
Hereinafter, the present invention will be described in more detail with reference to the
following Examples. However, these Examples are for illustrative purposes only, and
the invention is not intended to be limited by these Examples.
Example 1. Production of in vitro activated cell line
Example 1-1: Production of cell line showing cAMP response to GLP-1
PCR was performed using a region corresponding to ORF (Open Reading Frame) in cDNA
(OriGene Technologies, Inc. USA) of human GLP-1 receptor gene as a template, and the
following forward and reverse primers including each of the HindIII and EcoRI
restriction sites so as to obtain a PCR product.
Forward primer: 5'-CCCGGCCCCCGCGGCCGCTATTCGAAATAC-3'(SEQ ID NO. 47)
Reverse primer: 5'-GAACGGTCCGGAGGACGTCGACTCTTAAGATAG-3'(SEQ ID NO.
The PCR product was cloned into the known animal cell expression vector x0GC/dhfr to
prepare a recombinant vector x0GC/GLP1R.
CHO DG44 cell line cultured in DMEM/F12 (10% FBS) medium was transfected with the
recombinant vector x0GC/GLP1R using Lipofectamine (Invitrogen, USA), and cultured
in a selection medium containing 1 mg/mL G418 and 10 nM methotraxate. Single clone
cell lines were selected therefrom by a limit dilution technique, and a cell line showing
excellent cAMP response to GLP-1 in a concentration-dependent manner was finally
selected therefrom.
Example 1-2: Production of cell line showing cAMP response to glucagon
PCR was performed using a region corresponding to ORF in cDNA (OriGene Technologies,
Inc. USA) of human glucagon receptor gene as a template, and the following forward and
reverse primers including each of the EcoRI and XhoI restriction sites so as to obtain a
PCR product.
Forward primer: 5'-CAGCGACACCGACCGTCCCCCCGTACTTAAGGCC-3'
(SEQ ID NO. 49)
Reverse primer: 5'-CTAACCGACTCTCGGGGAAGACTGAGCTCGCC-3'(SEQ ID NO.
The PCR product was cloned into the known animal cell expression vector x0GC/dhfr to
prepare a recombinant vector x0GC/GCGR.
CHO DG44 cell line cultured in DMEM/F12 (10% FBS) medium was transfected with the
recombinant vector x0GC/GCGR using Lipofectamine, and cultured in a selection
medium containing 1 mg/mL G418 and 10 nM methotraxate. Single clone cell lines
were selected therefrom by a limit dilution technique, and a cell line showing excellent
cAMP response to glucagon in a concentration-dependent manner was finally selected
therefrom.
Example 2. Test on in vitro activity of oxyntomodulin derivatives
Example 2-1: Synthesis of oxyntomodulin derivatives
In order to measure in vitro activities of oxyntomodulin derivatives, oxyntomodulin
derivatives having the following amino acid sequences were synthesized (Table 1).
Table 1
Oxyntomodulin and oxyntomodulin derivatives
SEQ ID NO. Amino acid sequence
SEQ ID NO. 1 HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA
SEQ ID NO. 2 CA-SQGTFTSDYSKYLDEEAVRLFIEWLMNTKRNRNNIA
SEQ ID NO. 3 CA-SQGTFTSDYSKYLDERRAQDFVAWLKNTGPSSGAPPPS
SEQ ID NO. 4 CA-GQGTFTSDYSRYLEEEAVRLFIEWLKNGGPSSGAPPPS
SEQ ID NO. 5 CA-GQGTFTSDYSRQMEEEAVRLFIEWLKNGGPSSGAPPPS
SEQ ID NO. 6 CA-GEGTFTSDLSRQMEEEAVRLFIEWAAHSQGTFTSDYSKYL
SEQ ID NO. 7 CA-SQGTFTSDYSRYLDEEAVRLFIEWLMNTK
SEQ ID NO. 8 CA-SQGTFTSDLSRQLEEEAVRLFIEWLMNK
SEQ ID NO. 9 CA-GQGTFTSDYSRYLDEEAVXLFIEWLMNTKRNRNNIA
SEQ ID NO. 10 CA-SQGTFTSDYSRQMEEEAVRLFIEWLMNGGPSSGAPPPSK
SEQ ID NO. 11 CA-GEGTFTSDLSRQMEEEAVRLFIEWAAHSQGTFTSDYSRYL
SEQ ID NO. 12 CA-SQGTFTSDYSRYLDGGGHGEGTFTSDLSKQMEEEAVK
SEQ ID NO. 13 CA-SQGTFTSDYSRYLDXEAVXLFIEWLMNTK
SEQ ID NO. 14 CA-GQGTFTSDYSRYLDEEAVXLFIXWLMNTKRNRNNIA
SEQ ID NO. 15 CA-GQGTFTSDYSRYLDEEAVRLFIXWLMNTKRNRNNIA
SEQ ID NO. 16 CA-SQGTFTSDLSRQLEGGGHSQGTFTSDLSRQLEK
SEQ ID NO. 17 CA-SQGTFTSDYSRYLDEEAVRLFIEWIRNTKRNRNNIA
SEQ ID NO. 18 CA-SQGTFTSDYSRYLDEEAVRLFIEWIRNGGPSSGAPPPSK
SEQ ID NO. 19 CA-SQGTFTSDYSRYLDEEAVKLFIEWIRNTKRNRNNIA
SEQ ID NO. 20 CA-SQGTFTSDYSRYLDEEAVKLFIEWIRNGGPSSGAPPPSK
SEQ ID NO. 21 CA-SQGTFTSDYSRQLEEEAVRLFIEWVRNTKRNRNNIA
SEQ ID NO. 22 DA-SQGTFTSDYSKYLDEKRAKEFVQWLMNTK
SEQ ID NO. 23 HAibQGTFTSDYSKYLDEKRAKEFVCWLMNT
SEQ ID NO. 24 HAibQGTFTSDYSKYLDEKRAKEFVQWLMNTC
SEQ ID NO. 25 HAibQGTFTSDYSKYLDEKRAKEFVQWLMNTC
SEQ ID NO. 26 HAibQGTFTSDYSKYLDEKRAKEFVQWLMNTC
SEQ ID NO. 27 HAibQGTFTSDYSKYLDEQAAKEFICWLMNT
SEQ ID NO. 28 HAibQGTFTSDYSKYLDEKRAKEFVQWLMNT
SEQ ID NO. 29 CA-AibQGTFTSDYSKYLDEKRAKEFVQWLMNTC
SEQ ID NO. 30 HAibQGTFTSDYAKYLDEKRAKEFVQWLMNTC
SEQ ID NO. 31 YAibQGTFTSDYSKYLDEKRAKEFVQWLMNTC
In Table 1, amino acids in bold and underlined represent ring formation, and amino acids
represented by X mean a non-native amino acid, alpha-methyl-glutamic acid. In
addition, CA represents 4-imidazoacetyl, and DA represents desamino-histidyl.
Example 2-2: Test on in vitro activity of oxyntomodulin derivatives
In order to measure anti-obesity efficacies of the oxyntomodulin derivatives synthesized in
Example 2-1, cell activity was measured in vitro using the cell lines prepared in
Examples 1-1 and 1-2.
The cell lines were those prepared by transfecting CHO (Chinese Hamster Ovary) to
express human GLP-1 receptor gene and glucagon receptor gene, respectively. Thus,
they are suitable to measure GLP-1 and glucagon activities. Therefore, the activity of
each oxyntomodulin derivative was measured using each transformed cell line.
Specifically, each cell line was sub-cultured twice or three time a week, and aliquoted in
each well of a 96-well plate at a density of 1 X 10 , followed by cultivation for 24 hours.
The cultured cells were washed with KRB buffer and suspended in 40 ml of KRB buffer
containing 1 mM IBMX, and left at room temperature for 5 minutes. Oxyntomodulin
(SEQ ID NO. 1) and oxyntomodulin derivatives (represented by SEQ ID NOs. 2-6, 8,
-13, 17, 18, 23-25, 27-30 and 31) were diluted from 1000 nM to 0.02 nM by 5-fold
serial dilution, and each 40 mL thereof was added to the cells, and cultured at 37°C for 1
hour in a CO2 incubator. Then, 20 mL of cell lysis buffer was added for cell lysis, and
the cell lysates were applied to a cAMP assay kit (Molecular Device, USA) to measure
cAMP concentrations. EC values were calculated therefrom, and compared to each
other. EC values are shown in the following Table 2.
Table 2
Table 2
Comparison of in vitro activities for GLP-1 receptor and glucagon receptor between
oxyntomodulin and oxyntomodulin derivatives
SEQ ID NO. EC (nM)
SEQ ID NO. CHO/GLP-1R CHO/GCGR
SEQ ID NO. 1 50 - 210 10 - 43
SEQ ID NO. 2 51.8 12.8
SEQ ID NO. 3 >1,000 637.7
SEQ ID NO. 4 5.5 >1,000
SEQ ID NO. 5 5.9 >1,000
SEQ ID NO. 6 500.1 >1,000
SEQ ID NO. 8 419.6 >1,000
SEQ ID NO. 10 >1,000 >1,000
SEQ ID NO. 11 >1,000 >1,000
SEQ ID NO. 12 >1,000 >1,000
SEQ ID NO. 13 >1,000 >1,000
SEQ ID NO. 17 97.9 >1,000
SEQ ID NO. 18 96.3 >1,000
SEQ ID NO. 23 2.46 5.8
SEQ ID NO. 24 1.43 6.95
SEQ ID NO. 25 1.9 1.3
SEQ ID NO. 27 2.8-5.5 3.1-5.6
SEQ ID NO. 28 3.1 0.3
SEQ ID NO. 29 14.25 17.3
SEQ ID NO. 30 2.20 80.2
SEQ ID NO. 31 12.5 1.0
As shown in Table 2, there were oxyntomodulin derivatives showing excellent in vitro
activities and different ratios of activities on GLP-1 receptor and glucagon receptor,
compared to native oxyntomodulin of SEQ ID NO. 1.
It is known that oxyntomodulin activates both the GLP-1 receptor and glucagon receptor to
suppress appetite, facilitate lipolysis, and promote satiety, thereby showing anti-obesity
effects. The oxyntomodulin derivatives according to the present invention show higher
in vitro activities on both the GLP-1 receptor and glucagon receptor than the wild-type
oxyntomodulin, and therefore can be used as a therapeutic agent for obesity with higher
efficacies than the known oxyntomodulin.
Example 3. Test on in vivo activity of oxyntomodulin derivatives
In order to measure in vivo therapeutic activity of oxyntomodulin derivatives, changes in
food intake by administration of oxyntomodulin derivatives were examined in ob/ob
mouse using native oxyntomodulin as a control.
Specifically, obese diabetic ob/ob mice, commonly used to test the efficacies of therapeutic
agents for obesity and diabetes, were fasted for 16 hours, and administered with 1 or 10
mg/kg of oxyntomodulin, or 0.02, 0.1, 1 or 10 mg/kg of the oxyntomodulin derivative of
SEQ ID NO. 2. Then, food intake was examined for 2 hours (. is a
graph showing changes in food intake according to administration dose of oxyntomodulin
or oxyntomodulin derivative. As shown in administration of 1 mg/kg of
oxyntomodulin derivative showed more excellent inhibitory effects on food intake than
administration of 10 mg/kg of oxyntomodulin.
Taken together, the oxyntomodulin derivatives of the present invention have much higher
anti-obesity effects than the wild-type oxyntomodulin, even though administered at a
lower dose, indicating improvement in the problems of the wild-type oxyntomodulin that
shows lower anti-obesity effects and should be administered at a high dose three times a
day.
Claims (6)
1. A peptide comprising the amino acid sequence of SEQ ID NO: 4 or 5.
2. The peptide according to claim 1, comprising the amino acid sequence of SEQ ID NO: 4.
3. The peptide according to claim 2, comprising the amino acid sequence of SEQ ID NO: 5.
4. The peptide according to any one of the previous claims, wherein the peptide has anti-obesity effects.
5. A pharmaceutical composition comprising the peptide of any one of claims 1 to 4 as an active ingredient and a pharmaceutically acceptable carrier.
6. The pharmaceutical composition according to claim 5, wherein the composition further comprises one or more agents selected from a GLP-1 receptor agonist, a leptin receptor agonist, a DPP-IV inhibitor, a Y5 receptor antagonist, a melanin-concentrating hormone (MCH) receptor antagonist, a Y
Priority Applications (1)
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NZ755534A NZ755534B2 (en) | 2011-06-10 | 2012-06-07 | Novel oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same |
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Application Number | Priority Date | Filing Date | Title |
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KR10-2011-0056472 | 2011-06-10 | ||
KR20110056472 | 2011-06-10 | ||
NZ734808A NZ734808B2 (en) | 2011-06-10 | 2012-06-07 | Novel oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same |
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NZ748012B2 true NZ748012B2 (en) | 2020-05-01 |
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