CN102924589B - Analog of glucagon-like-peptide-2 (GLP-2) and its production and use - Google Patents
Analog of glucagon-like-peptide-2 (GLP-2) and its production and use Download PDFInfo
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Abstract
The present invention relates to a kind of new analog of GLP 2 and preparation method thereof, compared with natural GLP 2, the chemical stability of the compound of the present invention is improved, and remains the pharmacologically active of natural GLP 2 simultaneously.GLP 2 analog of the present invention has a following chemical constitution:
Description
Technical field
Analog that the present invention relates to glucagon-like-peptide-2 (GLP-2) and preparation method thereof and prevention and treat such as gastrointestinal
Associated conditions and the purposes in alleviating the side effect of chemotherapy and radiation therapy.
Background technology
GLP-2 belongs to Proglucagon and derives peptides (proglucagon-derived peptide, PGDP), is Proglucagon
One of product that (proglucagon, PG) is degraded by prohormone convertase (prohormone convertase, PC), by intestinal L
Secretory cell synthesis and release, and ingested, nerve and the factor such as endocrine regulate.
GLP-2 can specifically stimulate the growth of intestinal mucosa, strengthens the regeneration after intestinal mucosal injury；Suppression epithelium of intestinal mucosa is thin
Born of the same parents and the apoptosis of pit cell；Strengthen enterocyte substrate side to the transhipment of glucose and glucose transporter-2 (glucose
Transporter-2, GLUT2) expression, promote intestinal digestion and absorption function；Suppression digestive tract power and gastric acid secretion；Strengthen intestinal
Mucosal barrier function；Increase intestinal blood supply.
In addition to the nutrition of normal colonic mucosa and growth promoting function, GLP-2 can also accelerate the Regeneration and Repair after intestinal mucosal injury.
GLP-2 remains the adaptability proliferation response of intestinal segment mucosa after can remarkably promoting little Extensive resection of the small bowel, make intestinal tube diameter, crypts deep
Degree, height of naps, intestinal mucosa DNA and protein content substantially increase
GLP-2 is to be carried out by many different approach to the repair of intestinal mucosa and the mechanism of action of maintenance function of intestinal canal.
Under physiological situation, GLP-2 promotes the transport of enteral nutrition by suppression gastro-intestinal secretion and gastrointestinal motility, increases intestinal blood
Flow and promotion pit cell propagation, also strengthen the barrier function of intestinal, the apoptosis of suppression pit cell simultaneously.
The single chain polypeptide that GLP-2 is made up of 33 amino acid residues, molecular weight 3900 dalton, aminoacid sequence is in suckling
Animal has well-conserved, is the polypeptide with following sequence:
H-His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-P
he-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-OH.GLP-2 two acyl peptide peptidase IV (DPPIV) in the circulating cycle
Effect under amino-terminal crack rapidly and lose activity, and pass through renal metabolism.Due to the zymolysis of DPPIV, GLP-2's
Half-life is about 7 minutes (Tavares etc., Am.J.Physiol.Endocrinol.Metab.2000,278:134-139).
Although the small intestinal specificity that GLP-2 shows and the beneficial pharmacological effect that it has have caused the attention of people, but
Relative to the low stability of endogenous DPPIV, significantly limit the purposes of GLP-2.
WO9739031 discloses the analog of a kind of GLP-2, and 2 alanine are substituted by glycine, improves the stability of peptide.
CN101171262 discloses a kind of GLP-2 analog, be by wild-type sequence 8,16,24 and/or 28 or
The aminoacid of multiple positions is replaced, and/or 31 to 33 amino acids disappearances obtains, and is favorably improved the stability of polypeptide.
Summary of the invention
It is an object of the invention to provide the analog of a kind of GLP-2, compared with wild GLP-2, there is more stable chemical characteristic,
The longer half-life, the most still retain and there is the biological activity being similar to GLP-2.Its chemical structural formula is as follows:
The most each R1、R2Independent selected from H, alkyl, thiazolinyl, alkynyl, aryl alkyl, cycloalkyl-alkyl, heteroaryl alkyl or
Cycloheteroalkylalkyl；R1、R2Preferably alkyl, more preferably C1-C4Alkyl, most preferable；
R3Independent selected from alkyl, thiazolinyl, alkynyl, [R1′-K-R1′]n；
Described R1' selected from alkyl, alkynyl (thiazolinyl) or alkynyl；
Described K is O, S, SO, SO2, CO, CO2, CONR2' or
Described R2' it is H or alkyl；
N is the integer of 2-7.
R3Preferably thiazolinyl.
The analog of GLP-2 of the present invention preferably has a compound of having structure:
The most each R1、R2Independent selected from H, alkyl, thiazolinyl, alkynyl, aryl alkyl, cycloalkyl-alkyl, heteroaryl alkyl or
Cycloheteroalkylalkyl；Preferably alkyl, more preferably C1-C4Alkyl, most preferable；
N and m is respectively selected from the integer of 2-7, and preferably when n is 7, m is 4.
The analog of GLP-2 of the present invention more preferably has a compound of having structure:
The polypeptide compound of the present invention is on the basis of natural GLP-2, by the amino of two sites of its structure (11 with 18)
Acid organic group replaces, and mutually cyclization connects, and forms the polypeptide compound of the present invention, therefore, the peptide of the present invention
Thing has natural polypeptide secondary structure, and α helix degree increases so that it is closer to the construction features of endogenous GLP-2, more
Easily combine with target position, therefore improve the polypeptide analog tolerance to two acyltransferase polypeptide peptidase IV, reduce and be degraded in vivo
Possibility.Compared with natural GLP-2 sequence, the chemical stability of the polypeptide compound of the present invention is improved.And the present invention
Polypeptide compound remain the pharmacologically active of natural GLP-2.
The aminoacid in two sites of polypeptide compound of the present invention is particularly preferably respectively to have optically active (R)-2-amino-2-
Methyl-6-decylenic acid (i.e. R8 in Fig. 1) and (S)-2-amino-2-methyl-6-heptenoic acid (i.e. S5 in Fig. 1) replace, described
The polypeptide compound that obtains after cyclization each other by the way of chemical catalysis of substituent group.
Described substituent group is protected with Fmoc, participates in the synthesis of polypeptide, described Fmoc-(R)-2-amino-2-methyl-6-
Decylenic acid has a following chemical constitution:
Described Fmoc-(S)-2-amino-2-methyl-6-heptenoic acid has a following structure:
The method that another aspect provides preparation aforementioned polypeptides compound.Can use well known to those skilled in the art
Method, selecting sequence or synthesis step that order is different produce the material with following chemical constitution:
Described synthetic method includes: such as liquid phase synthesis or solid phase synthesis (SPPS) are prepared, preferably SPPS.Described
Solid phase synthesis can select normal polystyrene-benzene divinyl crosslinked resin, polyacrylamide, polyethylene-glycols resin
Deng, such as: Wang resin (Wang Resin), Fmoc-Pro-CTC resin etc., preferably Fmoc-Pro-CTC resin.This
The circulus of invention compound is to prepare by the way of catalyzed cyclization, and described catalyst may is that ruthenium catalyst, excellent
The catalyst of choosing is double (thricyclohexyl phosphorus) ruthenous chloride (Grubbs 1 of phenylmethylenest), or Grubbs 2st。
Another aspect of the present invention provides the pharmaceutical composition including aforementioned polypeptides compound.Described pharmaceutical composition comprises effectively
The polypeptide compound with said structure of amount and pharmaceutically acceptable carrier, described compositions can be according to known in this area
Technology is prepared, such as, mix with conventional pharmaceutic adjuvant, be prepared as the system of injection, injection, or topical
The dosage form etc. of agent type such as Emulsion, unguentum, cream or nose administration, or there is the preparation of slow release effect, such as microsphere, fat
Plastid etc..
" pharmaceutically acceptable carrier " of the present invention includes any pharmaceutic adjuvant, such as filler, diluent, figuration
Agent etc..Such as include but not limited to: lactose, sucrose, glucose, starch, cellulose family are (such as carboxymethyl cellulose, hydroxypropyl
Methylcellulose etc.), ethylene glycol, Oleum Glycines, Oleum sesami, ethanol, physiological saline solution, sterilized water, ethanol etc..Generally, medicine
On, acceptable carrier is water miscible pH buffer, such as citrate, phosphate etc.；Antioxidant can also be contained,
Stabilizer (such as aminoacid), antibacterial etc..
Another aspect of the present invention provides above-mentioned GLP-2 analog in the medicine of preparation prevention and treatment harmonization of the stomach intestinal associated conditions
Application.Described harmonization of the stomach intestinal associated conditions includes but not limited to: gastric ulcer, malabsorption syndrome, inflammatory enteritis, exedens
Colitis, injury of small intestine, infectious enteritis, infective enteritis, the injury of small intestine caused due to chemotherapy or radiotherapy, malnutrition
Relevant disease, such as apositia.
Accompanying drawing explanation
Fig. 1 is the preparation flow of the present invention preferred GLP-2 analog, and the R8 in Fig. 1 molecular formula is (R)-2-amino-2-methyl-6-
Decene base, S5 is (S)-2-amino-2-methyl-6-heptenyl
Fig. 2 is with the test of pesticide effectiveness result of the rat model research present invention preferred GLP-2 analog
Detailed description of the invention
Below example is for further illustrating technical scheme.Institute's band protection in description of the invention and embodiment
The amino acid monomer of base and other chemical reagent etc., all can buy from associated companies and obtain, the test side of unreceipted actual conditions
Method, condition can carry out routinely, or the condition as proposed by goods supplier is carried out.
The preparation of embodiment 1 GLP-2 analog
According to the conventional method of solid phase synthesis, the aminoacid of band protection group is connected on resin one by one, then uses catalyst ring
Closing, then slough protection group and cut from resin by polypeptide, preparation is such as the preferred GLP-2 analog of following formula:
1, solid phase synthesis
Select 0.45g Fmoc-Asp (OtBu)-Wang resin (substitution value: 0.33mmol/g) to prepare, use at ambient temperature
DMF soaks resin 60min, is arranged in order in synthesizer by the aminoacid protected with Fmoc and carries out activation connection,
Obtaining such as the product of compound 2 in Fig. 1, structure is:
2, catalyzed cyclization
The compound of above-mentioned steps gained is respectively rinsed twice, then with DCE (8ml) with DCM (20ml) and DCE (20ml) successively
Soak 30min, then by Grubbs 1st(25mg x 2,20mg/0.1mmol) adds in reactant mixture, and rocked at room temperature 3 is little
Time.Detect cyclisation situation with MS, if cyclisation is not exclusively, repeats this step, be generally repeated 2 times, it is thus achieved that target polypeptides chemical combination
Thing (0.978g).
3, excision resin
Reactant mixture step 3 obtained is placed in E solution (10ml), is stirred at room temperature 2.5 hours under nitrogen protection.Cross
Filter, removes filtrate, and filter cake TFA (4ml) rinses, and is then placed over precipitation in cold ether (50ml), centrifugal；Obtain
Filter cake rinses twice with cold ether (100ml), vacuum drying, it is thus achieved that the polypeptide compound 468mg of the present invention, productivity 80.8%,
MW=3859.32
4, purification
Above-mentioned crude product HPLC is purified, it is thus achieved that sterling 35mg of purity more than 95%.
Embodiment 2 DPP IV (DPP-IV) resistant determination
2.5 μ l are contained the restructuring of 0.125mU by detection rGLP-2 and the DPP-IV resistance of the GLP-2 analog of embodiment 1
People DPP-IV (purchased from ProSpec) is dissolved in 20mM Tris-HCl buffer (pH 8), 100mM NaCl, 1mM EDTA,
In 10% glycerite, add the PBS solution (pH7.4) of the 50ul peptide to be measured containing 0.2mg/ml.In 37 DEG C of circulator baths
It is incubated 24 hours, adds the PBS solution quencher insulation of the 50ul diprotinA (purchased from BIOPRC) containing 4mg/ml.With
Anti-phase (PR) HPLC analyzes every kind of sample: the incubation mixture of 90ul quencher is expelled to Dynamax (purchased from Rainin)
On 300A, C5 (5 microns, 4.6*250 millimeter) post, the sample linear gradient of the acetonitrile modified water containing 0.1%TFA is carried out
Eluting, flow velocity 1ml/min, detects sample composition, by the peak area corresponding to remaining indigested parent peptide at 214nm
Measure cutting degree.Result shows, after being incubated 24 hours, the comparison rGLP-2 of about 25% is cut by DPP-IV, and does not examines
Measure the cleaved products of embodiment 1GLP-2 analog.
The pharmacodynamic evaluation of embodiment 3 GLP-2 analog
Select normal male SD rat (200+-20g), be randomly divided into 3 groups, 6/group, respectively PBS control group, rGLP-2
Group, embodiment 1GLP-2 analog group.It is administered according to 0.5mg/kg/day, abdominal part hypodermic, is administered 10 days, put to death,
Taking small intestinal, normal saline cleans, and weighs.Result such as Fig. 2 shows, compared with PBS group, and rGLP-2 group, embodiment 1
GLP-2 analog group all can be obviously promoted intestinal growth.
Claims (9)
1. an analog of GLP-2, its chemical structural formula is as follows:
2. the method for the analog preparing GLP-2 described in claim 1, it is characterised in that:
(1) preparation has the material of following structure
(2) by the compound of catalyst processing steps (1) so that it is cyclization.
3. method as claimed in claim 2, it is characterised in that step (1) is prepared by solid phase synthesis technique.
4. method as claimed in claim 3, it is characterised in that step (1) uses the solid phase synthesis technique of Fmoc protection.
5. method as claimed in claim 2, it is characterised in that the catalyst of step (2) is ruthenium catalyst.
6. method as claimed in claim 5, it is characterised in that described ruthenium catalyst is Grubbs 1st。
7. the purposes during the analog of the GLP-2 described in claim 1 prevents, treats the medicine of harmonization of the stomach intestinal associated conditions in preparation
。
8. purposes as claimed in claim 7, it is characterised in that described harmonization of the stomach intestinal associated conditions includes: malabsorption is comprehensive
Levy, inflammatory enteritis, the injury of small intestine caused due to chemotherapy or radiotherapy, malnutrition.
9. a pharmaceutical composition, including analog and the pharmaceutically acceptable load of the GLP-2 described in the claim 1 of effective dose
Body.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998003547A1 (en) * | 1996-07-19 | 1998-01-29 | 1149336 Ontario Inc. | Antagonists of intestinotrophic glp-2 peptides |
| EP1231219A1 (en) * | 1996-04-12 | 2002-08-14 | 1149336 Ontario Inc. | GLucagon-like peptide-2 analogs |
| WO2006117565A3 (en) * | 2005-05-04 | 2007-01-11 | Zealand Pharma As | Glucagon-like-peptide-2 (glp-2) analogues |
-
2011
- 2011-08-11 CN CN201110230173.9A patent/CN102924589B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1231219A1 (en) * | 1996-04-12 | 2002-08-14 | 1149336 Ontario Inc. | GLucagon-like peptide-2 analogs |
| WO1998003547A1 (en) * | 1996-07-19 | 1998-01-29 | 1149336 Ontario Inc. | Antagonists of intestinotrophic glp-2 peptides |
| WO2006117565A3 (en) * | 2005-05-04 | 2007-01-11 | Zealand Pharma As | Glucagon-like-peptide-2 (glp-2) analogues |
Non-Patent Citations (1)
| Title |
|---|
| Glucagon-like peptide-2: update of the recent clinical trials.;Jeppesen PB.等;《Gastroenterology.》;20060228;全文 * |
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