NZ717174B2 - 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
- NZ717174B2 NZ717174B2 NZ717174A NZ71717412A NZ717174B2 NZ 717174 B2 NZ717174 B2 NZ 717174B2 NZ 717174 A NZ717174 A NZ 717174A NZ 71717412 A NZ71717412 A NZ 71717412A NZ 717174 B2 NZ717174 B2 NZ 717174B2
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- seq
- peptide
- oxyntomodulin
- obesity
- glp
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
Abstract
Discloses a peptide comprising the amino acid sequence of SEQ ID NO:2 (CA-SQGTFTSDYSKYLDEEAVRLFIEWLMNTKRNRNNIA) for the prevention or treatment of obesity in a subject at risk of obesity or having obesity (where CA is 4-imidazoacetyl)
Description
Description
Title of Invention: NOVEL OXYNTOMODULIN DERIVATIVES AND
PHARMACEUTICAL COMPOSITION FOR TREATING OBESITY
COMPRISING THE SAME
Related Applications
This 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.
FILED 5.12.16
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)
FILED 5.12.16
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- I (GLP-1) is under development as a therapeutic agent for hy
perglycemia 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 oxyn-
tomodulin, 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 in
gredient 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 of Invention
Technical Problem
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.
Solution to Problem
The present invention provides a novel peptide showing excellent therapeutic effects on
obesity.
The present invention further provides a composition for the prevention or treatment of
obesity, comprising the peptide.
The present invention further provides a method for preventing or treating obesity by
administering the peptide or the composition to a subject.
The present invention further provides use of the peptide in the preparation of drugs for
the prevention or treatment of obesity.
The present invention further provides a peptide comprising the amino acid sequence of SEQ
ID NO:2
Advantageous Effects of Invention
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.
According to the invention there is also provided use of the peptide or the pharmaceutical
composition according to the invention for the manufacture of a medicament for the
prevention or treatment of obesity in a subject at risk of obesity or having obesity.
Brief Description of Drawings
is a graph showing changes in food intake according to administration dose of
oxyntomodulin or oxyntomodulin derivative.
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 , 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-
X18-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-
NO2), Phe(4-NH2), 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 ID NO: 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 (SEC 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-
X18-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;
XlO is glutamine, glutamic acid, lysine, arginine or is deleted;
Xl 1 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;
Xl 7 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;
[ 136] 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), HGEGTFTSDLSKQMEEEA VK (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.
[ 142] 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 m
creasing 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 oxyn
tomodulin. 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 oxyn
tomodulin (.
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 oxyn
tomodulin derivatives, they will show superior therapeutic effects to native oxyn
tomodulin. 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 oc-
currence 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 pre-
determined 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, in
travenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intra
pulmonary, 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 dys
function, 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 phar-
maceutically acceptable carrier, excipient, or diluent. As used herein, the term "pharma
ceutically 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 in
jectable preparations, the pharmaceutical composition may be formulated into an
ampule as a single dosage form or a multidose container. The pharmaceutical com
position 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 for-
mulation 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, sub
cutaneous, 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, an
tioxidants 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 ad-
ministered 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 pharma
ceutical 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 µg 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. According to 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 co
incident with the composition of this invention, and like factors well known in the
medical arts.
[ 171] In still another aspect, the present invention provides a use of the peptide or the phar-
maceutical composition including the same in the preparation of drugs for the
prevention or treatment of obesity.
Mode for the 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. 48)
The PCR product was cloned into the known animal cell expression vector
xOGC/dhfr to prepare a recombinant vector xOGC/GLPlR.
CHO DG44 cell line cultured in DMEM/F12 (10% PBS) medium was transfected
with the recombinant vector xOGC/GLPlR using Lipofectamine (Invitrogen, USA),
and cultured in a selection medium containing 1 mg/mL 0418 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 con
centration-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 Tech-
nologies, 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. 50)
The PCR product was cloned into the known animal cell expression vector
xOGC/dhfr to prepare a recombinant vector xOGC/GCGR.
CHO DG44 cell line cultured in DMEM/F12 (10% PBS) medium was transfected
with the recombinant vector xOGC/GCGR using Lipofectamine, and cultured in a
selection medium containing 1 mg/mL 0418 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
[Table l]
Oxyntomodulin and oxyntomodulin derivatives
SEQ ID NO. Aminoacidsequence
SEQ ID NO. 1 HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA
SEQ ID NO. 2 CA-SQGTFTSDYSKYLDEEA VRLFIEWLMNTKRNRNNIA
SEQ ID NO. 3 CA-SQGTFTSDYSKYLDERRAQDFV A WLKNTGPSSGAPPP
SEQ ID NO. 4 CA-GQGTFTSDYSRYLEEEA VRLFIEWLKNGGPSSGAPPPS
SEQ ID NO. 5 CA-GQGTFTSDYSRQMEEEA VRLFIEWLKNGGPSSGAPPP
SEQ ID NO. 6 CA-GEGTFTSDLSRQMEEEA VRLFIEW AAHSQGTFTSDYS
KYLD
SEQ ID NO. 7 CA-SQGTFTSDYSRYLDEEA VRLFIEWLMNTK
SEQ ID NO. 8 CA-SQGTFTSDLSRQLEEEA VRLFIEWLMNK
SEQ ID NO. 9 CA-GQGTFTSDYSRYLDEEA VXLFIEWLMNTKRNRNNIA
SEQIDN0.10 CA-SQGTFTSDYSRQMEEEA VRLFIEWLMNGGPSSGAPPP
SEQ ID NO. 11 CA-GEGTFTSDLSRQMEEEA VRLFIEW AAHSQGTFTSDYS
RYLDK
SEQ ID NO. 12 CA-SQGTFTSDYSRYLDGGGHGEGTFTSDLSKQMEEEA V
SEQ ID NO. 13 CA-SQGTFTSDYSRYLDXEA VXLFIEWLMNTK
SEQ ID NO. 14 CA-GQGTFTSDYSRYLDEEA VXLFIXWLMNTKRNRNNIA
SEQ ID NO. 15 CA-GQGTFTSDYSRYLDEEA VRLFIXWLMNTKRNRNNIA
SEQ ID NO. 16 CA-SQGTFTSDLSRQLEGGGHSQGTFTSDLSRQLEK
SEQ ID NO. 17 CA-SQGTFTSDYSRYLDEEA VRLFIEWIRNTKRNRNNIA
SEQ ID NO. 18 CA-SQGTFTSDYSRYLDEEA VRLFIEWIRNGGPSSGAPPPS
SEQ ID NO. 19 CA-SQGTFTSDYSRYLD E EAV K LFIEWIRN-
TKRNRNNIA
SEQ ID NO. 20 CA-SQGTFTSDYSRYLD E EA V K LFIEWIRNGG-
PSSGAPPPSK
SEQ ID NO. 21 CA-SQGTFTSDYSRQLEEEA VRLFIEWVRNTKRNRNNIA
SEQ ID NO. 22 DA-SQGTFTSDYSKYLD E KRA K EFVQWLMNTK
SEQ ID NO. 23 HAibQGTFTSDYSKYLDEKRAKEFVCWLMNT
SEQ ID NO. 24 HAibQGTFTSDYSKYLDEKRAKEFVQWLMNTC
SEQ ID NO. 25 HAibQGTFTSDYSKYLD E KRA K EFVQWLMNTC
SEQ ID NO. 26 HAibQGTFTSDYS K YLD E KRAKEFVQWLMNTC
E QAA K EFICWLMNT
SEQ ID NO. 27 HAibQGTFTSDYSKYLD
SEQ ID NO. 28 HAibQGTFTSDYSKYLDEKRAKEFVQWLMNT
SEQ ID NO. 29 CA-AibQGTFTSDYSKYLD E KRA K EFVQWLMNTC
SEQ ID NO. 30 HAibQGTFTSDY AKYLD E KRA K EFVQWLMNTC
SEQ ID NO. 31 Y AibQGTFTSDYSKYLD E KRA K EFVQWLMNTC
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 syn-
thesized 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 cul
tivation 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. Oxyn
tomodulin (SEQ ID NO. 1) and oxyntomodulin derivatives (represented by SEQ ID
NOs. 2-6, 8, 10-13, 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 C02 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
Table 2
[Table 2]
Comparison of in vitro activities for GLP-1 receptor and glucagon receptor between
oxyntomodulin and oxyntomodulin derivatives
SEQ ID NO. ECs (nM)
CHO/GLP-lR 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 >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
SEQIDN0.10
>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
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 oxyn
tomodulin 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 admin
istration 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 ad
ministered 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 (4)
1. A peptide comprising the amino acid sequence of SEQ ID NO:2.
2. A polynucleotide encoding the peptide of claim 1.
3. A pharmaceutical composition comprising the peptide of claim 1 as an active ingredient and a pharmaceutically acceptable carrier.
4. The pharmaceutical composition according to claim 3, wherein the composition further comprises one or more agents selected from the group consisting of 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)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NZ727090A NZ727090B2 (en) | 2011-06-10 | 2012-06-07 | Novel oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20110056472 | 2011-06-10 | ||
| KR10-2011-0056472 | 2011-06-10 | ||
| NZ618810A NZ618810B2 (en) | 2011-06-10 | 2012-06-07 | Novel oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ717174A NZ717174A (en) | 2017-07-28 |
| NZ717174B2 true NZ717174B2 (en) | 2017-10-31 |
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