NZ618810B2 - 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
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- NZ618810B2 NZ618810B2 NZ618810A NZ61881012A NZ618810B2 NZ 618810 B2 NZ618810 B2 NZ 618810B2 NZ 618810 A NZ618810 A NZ 618810A NZ 61881012 A NZ61881012 A NZ 61881012A NZ 618810 B2 NZ618810 B2 NZ 618810B2
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- New Zealand
- Prior art keywords
- seq
- peptide
- oxyntomodulin
- obesity
- receptor
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- C07K14/575—Hormones
-
- 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
- C07K14/575—Hormones
- C07K14/605—Glucagons
-
- 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: HAibQGTFTSDYSKYLDEKRAKEFVQWLMNTC and related pharmaceutical compositions and use to treat obesity.
Description
Description
Title of Invention: NOVEL OXYNTOMODULIN DERIVATIVES
AND PHARMACEUTICAL COMPOSITION FOR TREATING
OBESITY SING THE SAME
Technical Field
The present invention relates to a novel e 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 s in lifestyle are leading to s 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 ide die each
year as a result of being ight (World Health Organization, Global Strategy on
Diet, Physical Activity and Health, 2004).
Being overweight and obese increases blood pressure and cholesterol levels to cause
ence or exacerbation of various diseases such as cardiovascular disease,
diabetes, and arthritis, and are also main causes of rising incidence rates of arte
riosclerosis, hypertension, ipidemia or cardiovascular disease in children or ado
lescents as well as in adults.
Obesity is a severe condition that causes various diseases ide. It is thought to
be me by individual efforts, and it is also believed that obese patients lack ntrol.
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 ated 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 R i
monabant i-Aventis) shows a side-effect of central nerve er, 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 eutic 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
te and activates hormone-sensitive (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 h y
perglycemia in patients with diabetes, and it functions to stimulate insulin sis
and ion, 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 ed
to activate the GLP- 1 receptor, thereby ameliorating hyperglycemia in patients with
diabetes. However, anti-obesity drugs ing 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 e derived from a glucagon sor, pre-glucagon that binds to the
receptors of two peptides, GLP-1 and glucagon. modulin ents 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 d
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 ent of overweight human, which is administered via an oral,
parenteral, mucosal, rectal, subcutaneous, or transdermal route. However, it has been
ed 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 t 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-
al to se 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 e at position 17 to enhance resistance to protease, sub
stituting methionine with lysine at position 27 to enhance oxidative stability, and sub
stituting glutamine with aspartic acid and alanine at positions 20 and 24 and asparagine
with serine at position 28 to e deamidation stability. However, even though the
half-life of the dual agonist oxyntomodulin (Merck) was ed 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. Unfor
tunately, modulin or tives thereof have disadvantages of daily admin
istration of high dose due to the short half-life and low efficacy.
Disclosure of ion
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 s on obesity and to reduce its administration dose. As a
result, they found that the oxyntomodulin derivative shows more excellent ties on
a glucagon receptor and a GLP- 1 receptor than native oxyntomodulin, thereby
completing the present invention.
Solution to Problem
An object of the present invention is to provide a novel peptide showing excellent
therapeutic effects on y.
Another object of the t 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
ation of drugs for the prevention or treatment of obesity.
Advantageous Effects of Invention
Unlike native oxyntomodulin, the novel peptide of the t invention reduces food
intake, suppresses c 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 cy.
Brief Description of Drawings
is a graph showing changes in food intake according to administration dose of
modulin 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.
Rl -X 1-X2-GTFTSD-X3-X4-X5-X6-X7-X8-X9-X 10-X 11-X 12-X 13-X 14-X 15-X 16-
X17-X18-X19-X20-X21-X22-X23-X24-R2 (Formula 1)
wherein Rl is histidine, desamino-histidyl, dimethyl-histidyl (N-dimethyl-histidyl),
beta-hydroxyimidazopropionyl, 4-imidazoacetyl, beta-carboxy imidazopropionyl or
tyrosine;
X I is Aib(aminoisobutyric acid), d-alanine, glycine, Sar(N-methylglycine), serine, or
d-serine;
X2 is ic 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;
X I 1 is alanine, arginine, valine or is d;
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, ic acid, e 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;
X I8 is tryptophan or is deleted;
X19 is alanine, isoleucine, leucine, serine, valine or is deleted;
X20 is alanine, lysine, nine, ine, arginine or is deleted;
X21 is asparagine or is deleted;
X22 is alanine, glycine, ine 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 a-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 or and the glucagon receptor to show
anti-obesity effects. The peptide according to the present invention includes es,
peptide derivatives or peptide mimetics that are prepared by addition, deletion or sub
stitution 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 ing to the nomenclature rule of
IUPAC-IUB as follows:
Alanine A Arginine R
gine N Aspartic acid D
Cysteine C ic acid E
Glutamine Q Glycine G
Histidine H Isoleucine I
Leucine L Lysine K
Methionine M Phenylalanine F
Proline P Serine S
Threonine T phan W
Tyrosine Y Valine V
In the present invention, the peptide asses 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 ns, as well as atypical or non-naturally occurring amino acids
can be used. Commercially available sources of atypical amino acids e Sigma-
Aldrich, ChemPep Inc., and Genzyme Pharmaceuticals. The es including these
amino acids and atypical peptide ces 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 t invention may be sub
stituted with azoacetyl 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 ethyl-histidyl) where
the N-terminal amino group is modified with two methyl groups, beta-hydroxy imida
zopropionyl where the N-terminal amino group is substituted with a yl group, or
beta-carboxy imidazopropionyl where the N-terminal amino group is tuted 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 n-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 Me), Phe, Phe(4-Me), Phe(4-Cl), Phe(4-CN),
Phe(4-N0 2), Phe(4-NH 2), 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 ed. 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, tively 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 ion 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 (Formula 2)
In r specific embodiment, the peptide of the present invention is an oxyn
tomodulin derivative ing 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 (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 e,
Leu at position 26 which binds with GLP-1 receptor by hydrophobic ction is sub
stituted with the hydrophobic e, e or Val.
R1-SQGTFTSDYSKYLD-D1-D2-D3-D4-D5-LFVQW-D6-D7-N-D8-R3 (Formula
In still another specific ment, the peptide of the present invention is an oxyn
tomodulin 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 (Formula 5)
In Formulae 2 to 5, R l is the same as in the description of Formula 1;
A is selected from the group consisting of SQGTFTSDYSKYLDSRRAQDFVQWLMNT
(SEQ ID NO. 38), SDYSKYLDEEAVRLFIEWLMNT (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),
SDYSRYLEEEAVRLFIEWLKNG (SEQ ID NO. 41), SDYSRQMEEEAVRLFIEWLKNG
(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;
] Dl is serine, ic 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 cine, valine or serine;
] D7 is methionine, arginine or glutamine;
] D8 is threonine, glycine or alanine;
] El is serine, Aib, Sar, d-alanine or d-serine;
0] E2 is serine or glutamic acid;
1] E3 is arginine or lysine;
2] E4 is glutamine or ;
3] E5 is aspartic acid or glutamic acid;
4] E6 is glutamine, cysteine or lysine;
] E7 is cysteine, lysine or is deleted;
6] R3 is KRNRNNIA (SEQ ID NO. 32), GPSSGAPPPS (SEQ ID NO. 33) or
GPSSGAPPPSK (SEQ ID NO. 34);
7] R4 is HSQGTFTSDYSKYLD (SEQ ID NO. 35), HSQGTFTSDYSRYLDK (SEQ ID
NO. 36) or HGEGTFTSDLSKQMEEEAVK (SEQ ID NO. 37); and,
8] R5 is KRNRNNIA (SEQ ID NO. 32), GPSSGAPPPS (SEQ ID NO. 33),
GPSSGAPPPSK (SEQ ID NO. 34) or is d (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 a 6.
2] R1-X1-X2-GTFTSD-X3-X4-X5-X6-X7-X8-X9-X10-X1 1-X12-X13-X14-X15-X16-
X17-X18-X19-X20-X21-X22-X23-X24-R2 (Formula 6)
4] n Rl is ine, desamino-histidyl, 4-imidazoacetyl or tyrosine;
] X I is Aib(aminoisobutyric acid), glycine or serine;
6] X2 is glutamic acid or glutamine;
7] X3 is leucine or tyrosine;
8] X4 is serine or alanine;
9] X5 is lysine or arginine;
0] X6 is glutamine or tyrosine;
1] 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;
X I 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 d;
X16 is isoleucine, valine or is deleted;
X17 is alanine, cysteine, glutamic acid, glutamine, alpha-methyl-glutamic acid or is
deleted;
X I8 is phan or is d;
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 ting 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 d (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 ed from the group
consisting of the peptides of SEQ ID NOs. 1 to 31. Much more preferably, the peptide
of the present ion may be an oxyntomodulin derivative described in Table 1 of
e 2-1.
Oxyntomodulin has activities of two peptides, GLP-1 and glucagon. GLP-1
decreases blood glucose, s food intake, and sses gastric ng, and
glucagon increases blood glucose, facilitate lipolysis and decreases body-weight by in
creasing energy metabolisms. Different biological effects of two peptides can cause
red 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. ore, 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 ties 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 eutic effects on obesity than the conventional oxyn
lin. 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 cation
with polymers such as PEG and sugar chain or fusion with albumin, transferrin, fatty
acid, and immunoglobulin in order to improve the eutic 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
The term "homology", as used herein for the polynucleotide, indicates sequence
similarity between wild-type amino acid sequences or wild-type nucleotide ces,
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 gy 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 ed into a vector and
expressed so as to obtain a large amount of the peptide.
In still r aspect, the present invention provides a pharmaceutical composition
for the prevention or treatment of obesity sing the e.
As used herein, the term "prevention" means all of the s 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 ed favorably by administration
of the peptide or the composition.
As used herein, the term "administration" means introduction of an amount of a pre-
ined substance into a patient by a certain suitable method. The ition of
the present invention may be stered via any of the common routes, as long as it
is able to reach a d tissue, for example, but is not limited to, intraperitoneal, in
travenous, intramuscular, subcutaneous, ermal, oral, topical, intranasal, ulmonary
, or intrarectal administration. However, since es 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 lic 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 ated with
incidence of cancer.
The pharmaceutical composition of the present invention may further include a phar
maceutically acceptable carrier, ent, or diluent. As used herein, the term "pharma
ceutically acceptable" means that the composition is sufficient to achieve the
eutic 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 ation or coincident with the
composition of this invention, and other factors known in medicine.
The pharmaceutical composition including the derivative of the t invention
may further include a pharmaceutically acceptable carrier. For oral stration, 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 ent, a
ant, 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 ceutical 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, e, ol, mannitol,
xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate,
m silicate, cellulose, methylcellulose, microcrystalline cellulose,
polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc,
magnesium stearate and mineral oils. In addition, the ceutical formulations may
further include s, 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 ated into a preparation useful for e drugs
according to the typical method in the pharmaceutical field so as to be administered by
an oral or eral route such as through skin, intravenous, intramuscular, intra
arterial, intramedullary, intramedullary, intraventricular, pulmonary, transdermal, sub
ous, 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, e or dextrans, an
tioxidants such as ascorbic acid or hione, 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 jig to 500 mg per 1 kg of body weight
of a t. However, the ive dose of the peptide is ined considering
s factors including patient's age, body weight, health conditions, gender, disease
severity, diet, and ion rate, in addition to administration route and treatment
frequency of the pharmaceutical composition. In view of this, those d in the art
may easily determine an effective dose suitable for the particular use of the pharma
ceutical composition of the present invention. The pharmaceutical composition
according to the present invention is not particularly limited to the formulation, and ad
ministration route and mode, as long as it shows the effects of the t invention.
The pharmaceutical composition of the t invention shows excellent in-vivo
duration of efficacy and titer, thereby remarkably reducing the number and frequency
of administration f.
Moreover, the pharmaceutical composition may be administered alone or in com
bination 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 d, and may include a GLP-1
receptor agonist, a leptin receptor agonist, a DPP-IV inhibitor, a Y5 receptor an
st, a Melanin-concentrating hormone (MCH) receptor antagonist, a Y2/3
receptor agonist, a MC3/4 receptor agonist, a c/pancreatic lipase inhibitor, a
5HT2c agonist, a b3A receptor agonist, an Amylin or agonist, a Ghrelin an
tagonist, and/or a Ghrelin receptor antagonist.
In still another aspect, the present invention provides a method for preventing or
ng y, sing the step of administering to a t the peptide or the
pharmaceutical composition including the same.
In the present ion, 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 t limitation.
The pharmaceutical composition including the peptide of the present invention is ad
ministered to a subject suspected of having obesity, thereby treating the subject ef
ely. The obesity is as described above.
The therapeutic method of the present invention may include the step of admin
istering 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
t 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 y, other drugs used in combination or co
incident with the composition of this invention, and like factors well known in the
medical arts.
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 es.
Example 1. Production of in vitro activated cell line
Example 1-1: tion of cell line showing cAMP response to GLP-1
PCR was performed using a region corresponding to ORF (Open g Frame) in
cDNA (OriGene Technologies, Inc. USA) of human GLP-1 receptor gene as a
template, and the following d and reverse primers including each of the Hindlll
and EcoRI restriction sites so as to obtain a PCR product.
d 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% FBS) medium was transfected
with the recombinant vector xOGC/GLPIR using Lipofectamine (Invitrogen, USA),
and cultured in a selection medium containing 1 mg/mL G418 and 10 nM
methotraxate. Single clone cell lines were ed therefrom by a limit dilution
que, and a cell line showing excellent cAMP response to GLP-1 in a con
centration-dependent manner was finally selected rom.
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 or gene as a template, and the following
d and reverse primers including each of the EcoRI and Xhol restriction sites so
as to obtain a PCR product.
Forward primer: CGACACCGACCGTCCCCCCGTACTTAAGGCC-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% FBS) medium was transfected
with the recombinant vector xOGC/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 on in a concentration-dependent manner was finally
selected therefrom.
e 2. Test on in vitro activity of oxyntomodulin derivatives
e 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 1]
Oxyntomodulin and oxyntomodulin derivatives
SEQIDNO. Aminoacidsequence
SEQ ID NO. 1 HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA
SEQ ID NO. 2 CA-SQGTFTSDYSKYLDEEAVRLFIEWLMNTKRNRNNIA
SEQ ID NO. 3 CA-SQGTFTSDYSKYLDERRAQDFVAWLKNTGPSSGAPPP
SEQ ID NO. 4 CA-GQGTFTSDYSRYLEEEAVRLFIEWLKNGGPSSGAPPPS
SEQ ID NO. 5 CA-GQGTFTSDYSRQMEEEAVRLFIEWLKNGGPSSGAPPP
SEQ ID NO. 6 CA-GEGTFTSDLSRQMEEEAVRLFIEWAAHSQGTFTSDYS
KYLD
SEQ ID NO. 7 CA-SQGTFTSDYSRYLDEEAVRLFIEWLMNTK
SEQ ID NO. 8 CA-SQGTFTSDLSRQLEEEAVRLFIEWLMNK
SEQ ID NO. 9 CA-GQGTFTSDYSRYLDEEAVXLFIEWLMNTKRNRNNIA
SEQ ID NO. 10 CA-SQGTFTSDYSRQMEEEAVRLFIEWLMNGGPSSGAPPP
SEQ ID NO. 1 1 CA-GEGTFTSDLSRQMEEEAVRLFIEWAAHSQGTFTSDYS
RYLDK
SEQ ID NO. 12 CA-SQGTFTSDYSRYLDGGGHGEGTFTSDLSKQMEEEAV
SEQ ID NO. 13 TFTSDYSRYLDXEAVXLFIEWLMNTK
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-SQGTFTSDYSRYLDEEAVRLFIEWIRNGGPSSGAPPPS
SEQ ID NO. 19 CA-SQGTFTSDYSRYLD E EAV K LFIEWIRN-
TKRNRNNIA
SEQ ID NO. 20 CA-SQGTFTSDYSRYLD E EAV K RNGG-
PSSGAPPPSK
SEQ ID NO. 2 1 CA-SQGTFTSDYSRQLEEEAVRLFIEWVRNTKRNRNNIA
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 MNTC
SEQ ID NO. 26 HAibQGTFTSDYS K YLD E KRAKEFVQWLMNTC
SEQ ID NO. 27 HAibQGTFTSDYSKYLD E QAA K EFICWLMNT
SEQ ID NO. 28 HAibQGTFTSDYSKYLDEKRAKEFVQWLMNT
SEQ ID NO. 29 CA-AibQGTFTSDYSKYLD E KRA K EFVQWLMNTC
SEQ ID NO. 30 HAibQGTFTSDYAKYLD E KRA K EFVQWLMNTC
SEQ ID NO. 3 1 YAibQGTFTSDYSKYLD E KRA K EFVQWLMNTC
In Table 1, amino acids in bold and underlined ent ring formation, and amino
acids represented by X mean a tive amino acid, alpha-methyl-glutamic acid. In
on, CA represents 4-imidazoacetyl, and DA represents desamino-histidyl.
Example 2-2: Test on in vitro activity of oxyntomodulin derivatives
In order to e anti-obesity cies of the oxyntomodulin derivatives syn
thesized in Example 2-1, cell activity was ed 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 105, followed by cu l
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 d 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 on receptor between
oxyntomodulin and oxyntomodulin derivatives
As shown in Table 2, there were oxyntomodulin derivatives showing excellent in
vitro activities and different ratios of activities on GLP—1 or and glucagon
receptor, compared to native oxyntomodulin of SEQ ID NO. 1.
It is known that oxyntomodulin tes both the GLP—1 receptor and glucagon
receptor to suppress appetite, facilitate lipolysis, and promote satiety, y 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 tives
In order to measure in vivo therapeutic activity of oxyntomodulin tives,
changes in food intake by administration of oxyntomodulin tives were examined
in ob/ob mouse using native modulin 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—
lin 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 tive. As shown in admin—
istration of 1 mg/kg of oxyntomodulin derivative showed more ent 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 (5)
1. A peptide comprising the amino acid sequence of: TFTSDYSKYLDEKRAKEFVQWLMNTC (SEQ ID NO:24).
2. The peptide according to claim 1, wherein Glu at position 16 and Lys at position 20, taken together, form a ring.
3. The peptide according to claim 1, n Lys at position 12 and Glu at position 16, taken together, form a ring.
4. A pharmaceutical ition comprising the e of any one of claims 1 to 3 as an active ingredient and a ceutically acceptable carrier.
5. The pharmaceutical composition according to claim 4, wherein the pharmaceutical formulation showing prophylactic or therapeutic effects on obesity is selected from the group consisting of a glucagon like peptide-1 receptor agonist, a leptin receptor agonist, a dipeptidyl peptidase-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 |
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NZ717174A NZ717174B2 (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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KR20110056472 | 2011-06-10 | ||
KR10-2011-0056472 | 2011-06-10 | ||
PCT/KR2012/004494 WO2012169798A2 (en) | 2011-06-10 | 2012-06-07 | Novel oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same |
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NZ618810B2 true NZ618810B2 (en) | 2016-07-01 |
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