WO2021203864A1 - 一种肠促胰岛素类似物及其制备方法和用途 - Google Patents
一种肠促胰岛素类似物及其制备方法和用途 Download PDFInfo
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- WO2021203864A1 WO2021203864A1 PCT/CN2021/078194 CN2021078194W WO2021203864A1 WO 2021203864 A1 WO2021203864 A1 WO 2021203864A1 CN 2021078194 W CN2021078194 W CN 2021078194W WO 2021203864 A1 WO2021203864 A1 WO 2021203864A1
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- Prior art keywords
- fatty acid
- long
- glucagon
- polypeptide
- incretin
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Definitions
- the present invention relates to the field of biotechnology. More specifically, the present invention relates to an incretin analog and its preparation method and use.
- Hyperglycemia is caused by defective insulin secretion or impaired biological effects, or both. Diabetes is generally divided into type 1 diabetes and type 2 diabetes in clinical practice. Symptoms of hyperglycemia exist for a long time in diabetes. Severe hyperglycemia can cause chronic damage and dysfunction of various tissues, especially eyes, kidneys, heart, blood vessels, and nerves, which threaten human health. Especially with the change of lifestyle and the aging of the population, diabetes and its complications have increasingly become an important threat to human health.
- the main categories of clinical treatment drugs for type 2 diabetes in the prior art include: biguanide diabetes drugs (metformin, or phenformin), sulfonylurea diabetes drugs (glibenclamide, glipizide, gliclazide) , Glipizide, Glimepiride, or Gliquidone), glucosidase inhibitor drugs (acarbose, voglibose, or miglitol), insulin sensitizers ( Ciglitazone, troglitazone, rosiglitazone, or pioglitazone), aldose reductase inhibitor drugs (asstatin, epalrestat, polasstat, or torestat), Insulin-releasing drugs (repaglinide), or nateglinide).
- biguanide diabetes drugs metalformin, or phenformin
- sulfonylurea diabetes drugs glibenclamide, glipizide, gliclazide
- Glipizide Glim
- GLP-1R human glucagon-like peptide-1 receptor
- Liraglutide Liraglutide
- Semeglutide Semeglutide
- Liraglutide is a chemically modified GLP-1 analog.
- the fatty acid hexadecanoic acid
- the fatty acid can bind to serum albumin. It is administered clinically once a day for two indications of hypoglycemic and weight loss.
- Somaglutide is that Aib at position 8 on the GLP-1 (7-37) chain replaces Ala, Arg at position 34 replaces Lys, and Lys at position 26 is connected to the octadecane fatty acid chain. Compared with liraglutide, somaglutide has a longer fatty acid chain and a higher affinity for serum albumin. It is clinically injected subcutaneously once a week.
- Diabetic patients are generally obese, and weight loss can significantly improve diabetes. Therefore, for GLP-1 analogs, weight loss is an important indicator. Although liraglutide is approved for the treatment of obesity, the actual weight loss is only about 5.6 kg. Clinically, the average weight loss of somaglutide (0.5mg) and somaglutide (1.0mg) treatment groups was 4.2kg and 5.5kg. At present, the weight loss of drugs used for obesity is generally about 5-10% (compared with placebo), that is, the overall average weight loss ratio does not exceed 10% of the patient's body weight (Rudolph L. Leibel et al., Diabetes, 64 (7) ): 2299-2309, 2015).
- the purpose of the present invention is to provide an incretin analog and its preparation method and application.
- an incretin analogue which comprises a glucagon-like polypeptide and a long-chain fatty acid linked to it; wherein, the amino acid sequence of the glucagon-like polypeptide is as follows: (I):
- X 10 is amino acid K
- X 40 is selected from the group OH or NH 2 .
- the long-chain fatty acid is a fatty acid containing 14-20 carbons; preferably a fatty acid containing 16-18 carbons; more preferably the long-chain fatty acid is a linear saturated monocarboxylic acid ; More preferably, the long-chain fatty acid is palmitic acid.
- the long-chain fatty acid is connected to the amino acid K of the peptide chain of the glucagon-like polypeptide; preferably, it is connected to the amino acid of X 10 ; preferably, the connection is For cross-linking.
- the glucagon-like polypeptide and the long-chain fatty acid are connected through a linker; preferably, the linker is capable of reacting with amino acid K and capable of reacting with the active group of the long-chain fatty acid Connector.
- the linker is a linker containing at least one (such as 1 to 6) units of - ⁇ glutamyl-(- ⁇ Glu-).
- the use of the incretin analog in preparing a composition is provided, and the composition is used for:
- GLP-1R human glucagon-like peptide-1 receptor
- GIPR glucose-dependent insulinotropic polypeptide receptor
- GCGR glucagon receptor
- the reduction of food intake, reduction of fat, reduction of body weight or reduction of blood sugar may be a non-therapeutic purpose.
- the metabolic diseases include: hyperglycemia-related metabolic diseases or hyperlipidemia-related metabolic diseases.
- the metabolic disease related to hyperglycemia includes diabetes or metabolic syndrome related to diabetes; preferably, the metabolic syndrome related to diabetes includes insulin resistance and glucose intolerance.
- the metabolic diseases related to hyperlipidemia include obesity, hyperlipidemia, fatty liver, hypertriglyceridemia, hypercholesterolemia, low HDL cholesterol, and high LDL cholesterol; preferably,
- the fatty liver includes non-alcoholic fatty liver disease (NAFLD), and more preferably includes non-alcoholic fatty liver disease (NASH).
- NAFLD non-alcoholic fatty liver disease
- NASH non-alcoholic fatty liver disease
- composition which includes the aforementioned incretin analogue and a carrier; the carrier is a pharmaceutically, food, or health care acceptable carrier.
- the incretin analog is an effective amount.
- the composition includes, but is not limited to: a pharmaceutical composition, a food composition, or a health care product composition.
- glucagon-like polypeptide for preparing the incretin analog of claim 1, whose amino acid sequence is as shown in formula (I):
- X 10 is amino acid K
- X 40 is selected from the group OH or NH 2 .
- a polynucleotide encoding the glucagon-like polypeptide, an expression vector containing the polynucleotide and/or a recombinant cell containing the polynucleotide.
- a method for preparing the incretin analogue which comprises: linking the glucagon-like polypeptide with a long-chain fatty acid.
- a non-therapeutic method for reducing food intake, reducing fat, reducing body weight, or reducing blood sugar including administering to a subject who needs to reduce food intake, reducing fat, reducing body weight, or reducing blood sugar
- the said incretin analogue, or the said composition including administering to a subject who needs to reduce food intake, reducing fat, reducing body weight, or reducing blood sugar.
- kits which comprises: the incretin analog; or comprises the composition.
- Figure 1 shows the mass spectrometric analysis results of the incretin analog P3YELAN.
- Figure 2 shows the incretin analog P3YELAN in vitro GLP-1R agonistic activity measurement results; dulaglutide as a control.
- Figure 3 shows the in vitro GIPR agonistic activity of the incretin analogue P3YELAN.
- Figure 4 shows the in vitro GCGR agonistic activity of the incretin analogue P3YELAN.
- Figure 5 shows the results of in vitro serum stability determination of the incretin analogue P3YELAN; YELAN and dulaglutide were used as controls.
- Figure 6 shows the results of random blood glucose changes of the incretin analogue P3YELAN in db/db mice; dulaglutide was used as a positive control; normal control (Normal control) was a normal unaffected animal; negative control (Negative control) It is a solvent control (no P3YELAN or positive control drug is given).
- Figure 7 shows the results of changes in body weight of the incretin analogue P3YELAN in DIO mice; Liraglutide was used as a positive control; the normal control (Normal control) was a normal animal without induced obesity; the negative control (Negative control) was a solvent control (Do not give P3YELAN or positive control drugs).
- Figure 8 shows the cumulative food intake changes of the incretin analog P3YELAN in DIO mice; liraglutide was used as a positive control; normal control was a normal animal without induced obesity; negative control was a solvent Control (no P3YELAN or positive control drug is given).
- Figure 9 shows the fasting blood glucose test results of the incretin analog P3YELAN in DIO mice; liraglutide was used as a positive control; the normal control (Normal control) was a normal animal without induced obesity; the negative control (Negative control) was a solvent Control (no P3YELAN or positive control drug is given).
- the present inventors provided an incretin analog based on in-depth research, which has both GLP-1R/GIPR/GCGR agonistic activity and has three effects. Agonists, which have significant effects in reducing blood sugar, fat and weight loss.
- the invention also provides its preparation method and application.
- the present invention provides an incretin analogue, which comprises a glucagon-like polypeptide and a long-chain fatty acid connected to it.
- sequence of the glucagon-like polypeptide used to establish the incretin analogue is (SEQ ID NO: 2):
- X 10 K
- X 40 is OH or NH 2 .
- the glucagon-like polypeptide of the present invention can be a recombinant polypeptide or a synthetic polypeptide. It can be a chemically synthesized product, or produced from a prokaryotic or eukaryotic host (for example, bacteria, yeast, higher plant, insect, and mammalian cells) using recombinant technology.
- a prokaryotic or eukaryotic host for example, bacteria, yeast, higher plant, insect, and mammalian cells
- the present invention also includes fragments, derivatives and analogs of the glucagon-like polypeptide shown in SEQ ID NO: 2.
- fragment refers to a polypeptide that substantially maintains the same biological function or activity as the glucagon-like polypeptide.
- the polypeptide fragment, derivative or analogue may be (i) one or more (such as 1-5, 1-3 or 1-2) conservative or non-conservative amino acid residues (preferably conservative amino acids) Residues) are substituted polypeptides, and such substituted amino acid residues may or may not be encoded by the genetic code, or (ii) in one or more (such as 1-5, 1-3 or 1-2 A) polypeptides with substitution groups in amino acid residues, or (iii) polypeptides formed by fusion of additional amino acid sequences to the polypeptide sequence (such as leader sequence or secretory sequence or sequence or proprotein sequence used to purify the polypeptide, Or fusion protein). According to the definition herein, these fragments, derivatives and analogs belong to the scope well known to those skilled in the art.
- the amino acid sequence of the glucagon-like polypeptide shown in SEQ ID NO: 2 has at least 75% (preferably at least 80%, 85%, 90%, 95%) sequence identity (sequence) identity), and has the function of the glucagon-like polypeptide shown.
- the present invention also includes modified forms of polypeptides (usually without changing the primary structure) formed by modifying one or several amino acids in order to increase the stability, half-life, and promote efficacy of the polypeptides, including: polypeptides in vivo or in vitro Chemically derived forms such as acetylation or carboxylation. Modifications also include glycosylation. Modified forms also include sequences with phosphorylated amino acid residues (such as phosphotyrosine, phosphoserine, phosphothreonine). It also includes polypeptides that have been modified to improve hydrolysis resistance or optimize solubility.
- the present invention also provides a polynucleotide sequence encoding the glucagon-like polypeptide of the present invention or a conservative variant polypeptide thereof.
- the polynucleotide of the present invention may be in the form of DNA or RNA.
- DNA can be a coding strand or a non-coding strand. That is, a "polynucleotide encoding a polypeptide" may include a polynucleotide encoding the polypeptide, or a polynucleotide that also includes additional coding and/or non-coding sequences.
- the present invention also relates to an expression vector containing the polynucleotide of the present invention, a host cell produced by genetic engineering using the expression vector or the coding sequence of a glucagon-like polypeptide, and a method for producing the polypeptide by recombinant technology.
- the present invention also provides the application of the glucagon-like polypeptide for preparing the incretin analog of the present invention.
- the long-chain fatty acid used to establish the incretin analog is a fatty acid containing 14 to 20 carbons, preferably a fatty acid containing 16 to 18 carbons.
- the ester, ether or derivative of the long-chain fatty acid is also included, and the salt (for example, sodium salt) of the long-chain fatty acid is also included.
- the long-chain fatty acid is a linear saturated monocarboxylic acid.
- connection is chemical cross-linking.
- the inventors introduced amino acids K or C on the basis of the original sequence of the polypeptide, and cross-linked fatty acids to K or C.
- glucagon-like polypeptide After the glucagon-like polypeptide is cross-linked with long-chain fatty acids, its activity is significantly improved and the half-life of the drug in the body is significantly prolonged.
- the fatty acid chain is palmitic acid (C16), which is a linear monocarboxylic acid, and its chemical structure is the group shown below:
- a linker may be provided between the glucagon-like polypeptide fragment and the long-acting carrier.
- the linker can usually be connected to the lysine residue K and/or cysteine residue C on the glucagon-like polypeptide fragment, and the active group on the long-acting carrier (for example, the linker may include a carboxyl group).
- Maleimide and other active groups react, so that the long-acting carrier and the incretin analog polypeptide fragment are respectively connected to the two ends of the linker to realize the cross-linking of the long-acting carrier and the incretin analog polypeptide fragment, For example, it can be various types of condensation reactions.
- the linker may be various linkers suitable for connecting the incretin analog polypeptide fragment and the long-acting carrier in the art.
- the linker may be - ⁇ Glu-(- ⁇ -glutamine Acyl-).
- the chemical structural formula is as follows:
- the C-terminal amino acid of the incretin analog provided by the present invention can be modified, such as amidation.
- the amidation usually refers to the conversion of the -COOH group at the C terminal to the -CONH 2 group, for example, in formula (I):
- X 40 is NH 2 .
- the specific sequence of the incretin analog is shown in SEQ ID NO: 6 in Table 1.
- Table 1 the sequence comparison of the polypeptide fragment and Glucagon (SEQ ID NO:1, referred to as GCG), GLP-1 (SEQ ID NO:3) and GIP (SEQ ID NO:4) are also presented.
- - ⁇ E- is - ⁇ Glu (- ⁇ -glutamyl-)
- ⁇ E-C16 means that palmitoyl is conjugated to the epsilon nitrogen of lysine via a - ⁇ -glutamyl-linker.
- 2xOEG means two -OEG-(-2-(2-(2-aminoethoxy)ethoxy)acetyl-) are connected.
- the present invention also provides a preparation method of the incretin analogue, which comprises linking the glucagon-like polypeptide with a long-chain fatty acid.
- the preparation method may include: using a chemical synthesis method to prepare the incretin analog; the preparation method may also include: culturing a suitable host cell under suitable conditions to express the incretin analog polypeptide Fragment, isolation and purification to obtain the incretin analog polypeptide fragment, and then the long-acting carrier is chemically cross-linked to the incretin analog polypeptide fragment.
- the incretin analog of the present invention can be prepared by standard peptide synthesis methods, for example, by standard solid-phase or liquid phase methods, stepwise or through fragment assembly, and separation and purification of the final incretin analog polypeptide fragment, incretin Insulin analog products, or any combination of recombinant and synthetic methods.
- the present invention also provides the use of the incretin analogs in the preparation of drugs for the treatment of metabolic diseases and GLP-1R/GIPR/GCGR pleiotropic agonists.
- the metabolic disease may specifically be selected from diabetes, obesity, dyslipidemia, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), other metabolic syndromes related to diabetes, including high triglycerides, Low HDL cholesterol and high LDL cholesterol, insulin resistance, obesity or glucose intolerance, etc.
- the present invention also provides a method for treating diseases, including the steps of: administering the incretin analog provided in the first aspect of the present invention to an individual.
- administering including the steps of: administering the incretin analog provided in the first aspect of the present invention to an individual.
- the diabetic model mice administered with the incretin analog of the present invention had significantly better hypoglycemic and weight loss effects than the control samples.
- the incretin analogs of the present invention can also be applied to some non-therapeutic aspects. According to the partial results of the embodiments of the present invention, it can be seen that the incretin analogs can significantly reduce food intake, lower fat, lower body weight, or lower blood sugar. Therefore, the incretin analogs of the present invention can also be applied to subjects who do not have disease characteristics but need to control food intake, reduce fat, and lose weight.
- the first is safety issues, especially immunogenicity issues.
- Anti-diabetic and weight-loss drugs need to be used for a long time and have extremely high safety requirements.
- the existing technical solutions often introduce more mutation sites, and often introduce unnatural amino acids and other modifications. These mutations and the introduction of unnatural amino acids all increase the risk of potential immunogenicity.
- the safety of drugs used to treat diseases such as diabetes and obesity is extremely important.
- Another example is the result of alanine scan that the second S is very important to retain GCG activity (only 1/3 of the activity is retained when mutated to Ala), but Brian Finan et al. reported (Finan B et al., Nat Med. 2015; 21 :27-36.), perform 2S ⁇ Aib, 2S ⁇ dSer, 2S ⁇ G, 2S ⁇ dAla substitution mutations on the second amino acid of GCG, and then combine the mutations at other positions, the relative agonistic activity of GCGR will increase instead It is 200% to 640%.
- Oxyntomodulin only has the 8 amino acids KRNRNNIA more than the C-terminal of Glucagon, and its GCGR agonistic activity is lost by about 90% (Alessandro Pocai et al., Diabetes; 58(10): 2258-2266, 2009; Henderson SJ et al., Diabetes Obes Metab, 2016).
- the incretin analogue provided by the present invention has extremely high GLP-1R and GIPR agonistic activity and slightly weaker GCGR agonistic activity. Surprisingly, the incretin analogue polypeptide has higher in vitro activity before and after fatty acid cross-linking. Is a significant change.
- the present invention also provides a composition containing an effective amount of the incretin analog of the present invention and a carrier; the carrier is a carrier that is acceptable in pharmacy, food science or health care products.
- the composition includes, but is not limited to: a pharmaceutical composition, a food composition, or a health care product composition.
- the pharmaceutical composition may contain 0.01-95% by weight (such as 0.1%, 1%, 5%, 10%, 20%, 30%, 50%, 80%, etc.).
- 0.01-95% by weight such as 0.1%, 1%, 5%, 10%, 20%, 30%, 50%, 80%, etc.
- pharmaceutically, food, or health care products acceptable are suitable for humans and/or animals without excessive adverse reactions (such as toxicity, irritation, and allergic reactions), that is, it is reasonable Substances with a high benefit/risk ratio; such as pharmaceutical carriers or excipients commonly used in this field.
- an effective amount or “effective dose” refers to those that can produce function or activity on humans and/or animals and can be accepted by humans and/or animals as used herein.
- the dosage form of the pharmaceutical composition of the present invention can be various, as long as it can make the active ingredient reach the mammalian body effectively.
- it can be selected from: gels, aerosols, tablets, capsules, powders, granules, syrups, solutions, or suspensions.
- those skilled in the art can choose a dosage form that is convenient for application.
- Suitable pharmaceutically acceptable carriers are well known to those of ordinary skill in the art. A full description of pharmaceutically acceptable carriers can be found in Remington’s Pharmaceutical Sciences (Mack Pub. Co., N.J. 1991).
- the pharmaceutically acceptable carrier in the composition may contain liquid, such as water, phosphate buffer, ringer solution, physiological saline, balanced salt solution, glycerol or sorbitol, and the like.
- auxiliary substances such as lubricants, glidants, wetting agents or emulsifiers, pH buffer substances and stabilizers, such as albumin, may also be present in these carriers.
- the preferred pharmaceutical compositions are solid compositions, especially tablets and solid-filled or liquid-filled capsules.
- the compound of the present invention or its pharmaceutical composition can also be stored in a sterile device suitable for injection or drip infusion.
- the effective administration dose of the incretin analogue of the present invention as an active ingredient may vary with the mode of administration and the severity of the disease to be treated, for example, it is administered at a dose of about 0.00001-10 mg/kg body weight per day.
- the administration time can also be adjusted, for example, when it is administered in a sustained-release form, the medicine can be administered every other day or at intervals of several days.
- the dosage regimen can be adjusted to provide the best therapeutic response.
- the effective dose of large animals or humans can be calculated by the corresponding professional conversion formula according to the dose of small animals (including solid or solution dose conversion).
- the present invention also provides a medicine kit or kit, which comprises: the incretin analog; or the pharmaceutical composition.
- the kit or kit of the present invention may also include other auxiliary accessories, such as a syringe.
- the kit or kit may also include instructions for use to facilitate the use by those skilled in the art in a correct manner.
- MOLECULAR CLONING A LABORATORY MANUAL, Second edition, Cold Spring Harbor Laboratory Press, 1989 and Third edition, 2001; Ausubel, etc., Current PROTOCOLS IN MOLECULAR BI, John Wi & Sons, New York, 1987 and periodic updates; the series METHODS IN ENZYMOLOGY, Academic Press, San Diego; Wolfe, CHROMATIN STRUCTURE AND FUNCTION, Third edition, Academic Press, San Diego, Vol. 304, ENZYMatinOLOGY, 1998; (PMWassarman and APWolffe, eds.), Academic Press, San Diego, 1999; and Methods IN MOLECULAR BIOLOGY, Vol. 119, Chromatin Protocols (PBBecker, ed.) Humana Press, Totowa, 1999, etc.
- Trt Trityl
- Boc tert-butoxycarbonyl
- HOBt 1-hydroxybenzotriazole
- DBLK 20% N,N-dimethylformamide piperidine
- TFA trifluoroacetic acid
- Fmoc-Lys(Pal-Glu-OtBu)-OH N ⁇ -fluorenyl methoxycarbonyl-(N ⁇ -( ⁇ -glutamyl (N ⁇ -hexadecyl, ⁇ -tert-butyl ester))) lysine acid;
- DIEA N,N-diisopropylethylamine
- Pd(PPh3)4 Tetra(triphenylphosphine) palladium
- Fmoc protecting group amino acid raw materials 2-CTC resin and Rink amide MBHA resin are all conventional commercially available reagents (protected amino acid manufacturer: Chengdu Zhengyuan Biochemical Technology Co., Ltd., resin manufacturer: Tianjin Nankai Hecheng Technology Co., Ltd.);
- the sources of organic solvents and other raw materials are commercially available (manufacturer: Sinopharm Chemical Reagent Co., Ltd.; chemically pure).
- Mass spectrometry The instrument model is 5800MALDI-TOF-TOF (AB SCIEX), the analysis software is TOF/TOF Explorer, Data Explorer, MS adopts Reflector Positive parameters: CID(OFF), mass rang(700-6500Da)FocusMass(1200Da)Fixed laser intensity(5600) Digitizer: Bin Size(0.5ns)
- the last amino acid is coupled, it is deprotected according to the above deprotection method. After the deprotection is complete, it is washed twice with DMF, twice with MeOH, twice with DCM, and twice with MeOH, each washing solvent is 20 mL. The material is collected and dried under reduced pressure at room temperature to obtain the target peptide resin.
- the synthesis of the branched protected amino acid is the same as that of P5YELAN, the first solid phase method is used to synthesize the branched protected amino acid W2: Alloc-Lys((Eicosanedioic Acidmono-tert-butylester)-Glu-OtBu)-OEG-OEG)-OH (where Fatty acid coupling adopts eicosandioic acid mono-tert-butyl ester), the structure is as follows:
- peptide synthesis is the same as P3YELAN, in which X 10 is coupled with W2, and Pd(PPh3)4 is used to remove the Alloc group.
- the obtained crude peptide was purified by RP-HPLC to obtain refined peptide (97.1%). MS determines the exact molecular weight of the refined peptide: m/z 4832.50 (M+H) + .
- GLP-1R agonistic activity detection uses the luciferase reporter gene detection method (Jonathan W Day, etc.: Nat Chem Biol. 2009 Oct; 5(10):749-57).
- the human GLP-1R gene was cloned into mammalian cell expression plasmid pCDNA3.1 to construct a recombinant expression plasmid pCDNA3.1-GLP-1R, and the full-length luciferase gene was cloned into pCRE plasmid to obtain pCRE-Luc Recombinant plasmid.
- the pcDNA3.1-GLP-1R and pCRE-Luc plasmids were transfected into CHO-K1 cells at a molar ratio of 1:10, and stable expression strains were selected.
- GIPR agonistic activity detection also uses luciferase reporter gene detection method.
- the human GIPR gene was cloned into mammalian cell expression plasmid pcDNA3.1, and the recombinant expression plasmid pCDNA3.1-GIPR was constructed, which was transfected with CHO-K1.
- the selection and construction of stable transfected cell lines were the same as above.
- the live measurement procedure was the same as above (positive control group: natural human GIP peptide), and the live measurement of each sample was repeated 3 times.
- the GCGR agonistic activity detection also uses the luciferase reporter gene detection method.
- the human GCGR gene was cloned into mammalian cell expression plasmid pcDNA3.1, and the recombinant expression plasmid pCDNA3.1-GCGR was constructed, which was transfected with CHO-K1.
- the selection and construction of stable transfected cell lines were the same as above.
- the live measurement procedure was the same as above (positive control group: natural human GCG peptide), and the live measurement of each sample was repeated 3 times.
- Figures 2, 3, and 4 are the results of the agonistic activity of GLP-1R, GIPR and GCGR, respectively.
- the specific EC50 is shown in Table 3.
- P3YELAN of the present invention has high GLP-1R and GIPR agonistic activity, as well as significant GCGR agonistic activity.
- P5YELAN and P9YELAN which have the same peptide sequence, have a significant decrease in cell agonistic activity due to the different fatty acid chains connected.
- the incretin analogs P3YELAN, YELAN and the reference substance (Dulaglutide) are prepared with 5mM Tris-HCl, pH8.5, 0.02% TWEEN-80 solution to a concentration of 1.0mg/ml, and sterilized and filtered (0.22 ⁇ m , Millipore SLGP033RB), dilute with rat serum 10 times, mix well, and dispense into sterile centrifuge tubes;
- Figure 5 shows the results of the residual activity of the incretin analogue P3YELAN over time. The results showed that compared with YELAN and Dulaglutide, P3YELAN maintained higher GLP-1R agonistic activity for a long time.
- db/db mice were screened according to three indicators: body weight, non-fasting blood glucose, and pre-medicine OGTT reaction, and grouped in a balanced manner. Each group had 6 mice. Excluding individuals who were too large or too small, the non-fasting blood glucose was greater than 15 mM.
- P3YELAN is dissolved in 50mM phosphate buffer (pH7.4), 5% sorbitol, 0.02%v/v Tween-80, subcutaneously injected dulaglutide or P3YELAN (multiple administration), the dose of dulaglutide is 10nmol /kg/4d, P3YELAN uses low (1nmol/kg/d), medium (3nmol/kg/d), and high dose (6nmol/kg/d). Random blood glucose of all animals was monitored daily from day0-day4, and random blood glucose was measured every 4 days afterwards. The measurement dates were arranged on day6, 10, 14, 18, 22, 26, 30, and 34.
- DIO mouse model Male C57BL/6J male mice aged about 7 weeks were given high-fat diet (60% kcal from fat) for about 16 weeks (23 weeks in total), and the test was performed when the body weight was about 45 g. The DIO mice were randomly divided into groups, 6 in each group, with no difference in basic body weight, and they were weighed every day. P3YELAN, liraglutide or PBS were injected subcutaneously. The dosage of Liraglutide is 40nmol/kg/d; the glucagon derivatives are low (5nmol/kg/d) and high dosage (20nmol/kg/d).
- the fasting blood glucose measurement results of the test animals are shown in Figure 9.
- the results show that P3YELAN of the three dose groups can significantly reduce the fasting blood glucose of the test animals, and its effect of reducing fasting blood glucose is better than that of liraglutide.
- the P3YELAN peptide of the present invention effectively overcomes some technical defects in the prior art, and has good industrial application value.
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Abstract
Description
Claims (10)
- 一种肠促胰岛素类似物,其包括类胰高血糖素多肽以及与之相连的长链脂肪酸;其中,所述的类胰高血糖素多肽的氨基酸序列如式(I):YSEGTFTSDX 10SKYLDSQAAQDFVQWLLAGGPSSGAPPPSX 40(I);式(I)中,X 10为氨基酸K,X 40选自基团OH或NH 2。
- 如权利要求1所述的肠促胰岛素类似物,其特征在于,所述的长链脂肪酸为含有14~20个碳的脂肪酸;较佳地为含有16~18个碳的脂肪酸;更佳地所述长链脂肪酸为直链饱和一元羧酸;更佳地,所述的长链脂肪酸为棕榈酸。
- 权利要求1~3任一所述的肠促胰岛素类似物在制备组合物中的用途,所述的组合物用于:激活人胰高血糖素样肽-1受体,葡萄糖依赖性促胰岛素多肽受体和/或胰高血糖素受体;预防、缓解或治疗代谢性疾病;或减少食物摄入、降低脂肪、降低体重或降低血糖。
- 如权利要求4所述的用途,其特征在于,所述的代谢性疾病包括:高血糖相关的代谢性疾病或高血脂相关的代谢性疾病;较佳地,所述高血糖相关的代谢性疾病包括:糖尿病或与糖尿病相关的代谢综合 症;较佳地,所述与糖尿病相关的代谢综合症包括胰岛素抵抗、葡萄糖耐受不良;或所述高血脂相关的代谢性疾病包括:肥胖、高血脂、脂肪肝、高甘油三酯血症、高胆固醇血症、低HDL胆固醇、高LDL胆固醇;较佳地,所述的脂肪肝包括非酒精性脂肪肝病,更佳地包括非酒精性脂肪肝炎。
- 一种组合物,其包括权利要求1~3任一所述的肠促胰岛素类似物,以及载体;所述的载体为药学上、食品学上或保健品学上可接受的载体。
- 一种用于制备权利要求1所述的肠促胰岛素类似物的类胰高血糖素多肽,其氨基酸序列如式(I):YSEGTFTSDX 10SKYLDSQAAQDFVQWLLAGGPSSGAPPPSX 40(I);式(I)中,X 10为氨基酸K,X 40选自基团OH或NH 2。
- 一种制备权利要求1所述的肠促胰岛素类似物的方法,包括:将权利要求7所述的类胰高血糖素多肽与长链脂肪酸相连;较佳地,所述的长链脂肪酸为含有14~20个碳的脂肪酸;更佳地为含有16~18个碳的脂肪酸;更佳地所述长链脂肪酸为直链饱和一元羧酸;更佳地,所述的长链脂肪酸为棕榈酸;较佳地,所述长链脂肪酸连接于所述类胰高血糖素多肽的肽链的氨基酸K上;更佳地,连接于X 10的氨基酸上;更佳地,所述的连接为交联;较佳地,所述类胰高血糖素多肽与所述长链脂肪酸通过接头连接;更佳地,所述接头是能与氨基酸K反应,且能与长链脂肪酸的活性基团反应的接头;更佳地,所述的接头为包含至少1个单位的-γ谷氨酰-的接头。
- 一种非治疗性地减少食物摄入、降低脂肪、降低体重或降低血糖的方法,包括给予需要减少食物摄入、降低脂肪、降低体重或降低血糖的受试者权利要求1~3任一所述的肠促胰岛素类似物,或权利要求6所述的组合物。
- 一种药盒,其中包含:权利要求1~3任一所述的肠促胰岛素类似物;或权利要求6所述的组合物。
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CN109776670A (zh) * | 2012-12-11 | 2019-05-21 | 米迪缪尼有限公司 | 用于治疗肥胖症的胰高血糖素/glp-1激动剂 |
CN109836488A (zh) * | 2017-11-24 | 2019-06-04 | 浙江道尔生物科技有限公司 | 一种治疗代谢疾病的胰高血糖素类似物 |
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