CN115490760A - GLP-1 receptor and GCG receptor co-agonist polypeptide derivative - Google Patents
GLP-1 receptor and GCG receptor co-agonist polypeptide derivative Download PDFInfo
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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Abstract
The GLP-1 receptor and GCG receptor co-agonist polypeptide provided by the invention has balanced GLP-1 receptor and GCG receptor agonistic activity, has prolonged action time, can be used for treating diabetes, and has remarkable and excellent weight loss effect.
Description
Technical Field
The invention relates to the technical field of polypeptide derivatives and application thereof, in particular to a GLP-1 receptor and GCG receptor co-agonist polypeptide derivative.
Background
Diabetes is a metabolic disorder disease such as carbohydrate, protein, fat and the like caused by the absolute or relative insulin secretion deficiency and/or insulin utilization disorder, takes hyperglycemia as a main marker, and can be caused by various factors such as heredity, environment and the like. Diabetes is largely classified into type 1 diabetes and type 2 diabetes, with the majority of patients being type 2 diabetes patients (statistically, about 90%). Type 2 diabetes (T2 DM), formerly known as non-insulin dependent diabetes mellitus (NIDDM) or adult-onset diabetes (adult-onset diabetes), is characterised by hyperglycemia, relative insulin deficiency, insulin resistance, etc. At present, the clinically used medicaments for treating type 2 diabetes mainly comprise biguanides, sulfonylureas, thiazolidinediones, DPP-4 receptor inhibitors, SGLT-2 receptor inhibitors and GLP-1 derivatives. Among them, GLP-1 derivatives have a similar hypoglycemic effect to insulin but almost no risk of hypoglycemia, and have both weight loss effect and cardiovascular protection function, and thus are becoming the main therapeutic drugs and research hotspots for type 2 diabetes.
GLP-1 (glucagon-like peptide-1) is a glucose-dependent hypoglycemic polypeptide hormone secreted by L cells of the terminal jejunum, ileum and colon, and has hypoglycemic effect after being specifically combined with GLP-1 receptor. GLP-1 has the main advantage of having a blood glucose dependent incretin secretion effect, avoiding the risk of hypoglycemia often existing in the treatment of diabetes. In addition to regulating blood glucose, GLP-1 may also prevent pancreatic beta cell degeneration, stimulate beta cell proliferation and differentiation, and may fundamentally improve the progression of diabetes. In addition, GLP-1 also has effects of inhibiting gastric acid secretion, delaying gastric emptying, and suppressing appetite, and has partial weight loss effect. However, if a better weight loss effect is to be achieved, the dosage is generally required to be increased, and the administration of a GLP-1 derivative at a high dose is liable to cause gastrointestinal side effects and tends to result in a narrow therapeutic window due to poor tolerability.
GCG (glucagon) is a hormone produced in α cells of the pancreas, and acts on the liver in a stress state such as cold or hunger of the body to decompose glycogen in the liver and increase blood glucose. It is well known for its ability to increase the acute degree of blood glucose by stimulating glycogenolysis and gluconeogenesis (Jiang & Zhang, am.J.Physio.l Endocrinol.Metab.284: E671-E678 (2003)). GCG actually has the effects of promoting fat degradation, fat oxidation, fever, etc. in vivo (Diabetologia, 2017,60, 1851-1861), and long-term administration can exhibit the effect of weight loss by increasing the amount of energy metabolism; repeated administration of glucagon was first reported decades ago to improve rodent metabolism while reducing rodent weight (Salter, am.j.clin.nutr.8:535-539 (1960)); however, the beneficial effects of GCG on energy metabolism have not been exploited because of its intrinsic hyperglycemic effect. Therefore, the invention develops the double-target co-agonist simultaneously having GLP-1 receptor and GCG receptor activation activities, and particularly realizes the remarkable enhancement of the GLP-1 single-target agonist in the aspect of weight-reducing efficacy by utilizing the functions of promoting fat degradation, fat oxidation and the like in the GCG body.
Oxyntomodulin (OXM) is a dual agonist of an endogenous GLP-1 receptor and a GCG receptor in a human body, has acute physiological effects including inhibition of gastric emptying, food intake, exocrine secretion of stomach and pancreas, promotion of resting energy consumption and the like, and has been proved by researches to have good effects of reducing blood sugar and losing weight in an animal model. Two separate and simultaneous papers report that the use of balanced GLP-1 receptor/GCG receptor co-agonists shows enhanced efficacy and safety in the treatment of rodent obesity relative to pure GLP-1 agonists, while improving glycemic control (Day et al nat. Chem. Biol.5:749-757 (2009); pocai et al Diabetes58:2258-2266 (2009)). However, some problems of Oxyntomodulin (OXM) itself, such as poor stability, low receptor activity, etc., cause the administration dosage to be larger, and limit the application.
Currently, the patent documents for the polypeptide GLP-1/GCG receptor dual agonist are: CN201911103118.6, CN201780013643.1, CN201680021972.6, cn201580030150.X, CN201380048137.8, WO2008/071972, WO2008/101017, WO2009/155258, WO2010/096052, WO2010/096142, WO2011/075393, WO2008/152403 and the like, but currently, no related dual agonist is on the market.
Therefore, the co-agonist polypeptide of GLP-1 and GCG receptors and the derivatives thereof with good effects of reducing blood sugar and weight still have great clinical requirements at present, especially on the aspect of having more excellent weight-reducing effect.
Disclosure of Invention
In order to solve the technical problems, the invention provides a GLP-1 receptor and GCG receptor co-agonist polypeptide derivative.
The term "GLP-1 analog" in the present invention refers to a polypeptide obtained by modifying a natural GLP-1 amino acid of a human, said modification comprising removal and/or substitution (substitution) and/or addition (elongation) of one or more amino acid residues, said amino acid(s) may be either a naturally occurring amino acid or an artificially synthesized amino acid.
In the present invention, the term "somaglutide" refers to a GLP-1 derivative having the peptide backbone and the overall compound structure in CAS registry No. 910463-68-2.
In the present invention, the term "receptor agonist" can be defined as a compound that binds to a receptor and elicits a response typical of natural ligands. A full agonist can be defined as an agonist that elicits a response of the same magnitude as the natural ligand (see, e.g., "Principles of Biochemistry", AL Lehninger, DL Nelson, MMCox, second edition, worth Publishers,1993, page 763). Thus, for example, a "GLP-1 receptor agonist" may be defined as a compound capable of binding to and activating the GLP-1 receptor.
In the present invention, the term "GCG receptor agonist" may be defined as a compound capable of binding to and activating the GCG receptor.
In the present invention, a "GLP-1 receptor and GCG receptor co-agonist polypeptide" can exhibit at least about 10% to about 500% or greater of the activity of native glucagon at the glucagon receptor, and also exhibit about at least 10% to about 200% or greater of the activity of native GLP-1 at the GLP-1 receptor.
In the present invention, the term "peptide" comprises a sequence of 3 or more amino acids, typically less than 50 amino acids, wherein the amino acids are naturally occurring or non-naturally occurring amino acids. Non-naturally occurring amino acids refer to amino acids that do not naturally occur in vivo, but which can be incorporated into the peptide structures described herein.
In the present invention, the term "derivative" with respect to a peptide (e.g., GLP-1 or GCG) means a chemically modified (e.g., covalently modified, etc.) peptide or an analog thereof. Typical modifications include amides, sugars, alkyl, acyl, esters, and the like.
In the present invention, the term "modification" of amino acid refers to substitution, addition or deletion of amino acid, including substitution or addition with any one of 20 kinds of amino acids commonly found in human protein and atypical or non-naturally occurring amino acid.
In the present invention, the term "aliphatic diacid" includes linear or branched aliphatic dicarboxylic acids having at least two carbon atoms and being saturated or unsaturated. Non-limiting examples of aliphatic diacids are succinic acid, adipic acid, suberic acid, sebacic acid, dodecanedioic acid, tetradecanedioic acid, hexadecanedioic acid, heptadecanedioic acid, octadecanedioic acid and eicosanedioic acid.
In the present invention, the term "pharmaceutically acceptable salt" refers to a salt of a polypeptide or protein that retains the biological activity of the parent.
In the present invention, the term "pharmaceutically acceptable excipient" broadly refers to any component other than the active therapeutic ingredient. The adjuvants may be inert substances, inactive substances and/or non-pharmaceutically active substances.
In a first aspect, the present invention provides a GLP-1 receptor and GCG receptor co-agonist polypeptide derivative or a pharmaceutically acceptable salt thereof, wherein the polypeptide has GLP-1 receptor and GCG receptor agonistic activity in balance, and the amino acid sequence of the polypeptide derivative or the pharmaceutically acceptable salt thereof is represented by the following formula:
X 1 X 2 X 3 GTFTSDYSX 12 YLX 15 X 16 X 17 X 18 AX 20 EFVX 24 WLLEGGPSSX 34
wherein:
X 1 selected from Y or H;
X 2 selected from I, V or S;
X 3 is selected from Q or H;
X 12 selected from R, K or S;
X 15 selected from E or D;
X 16 selected from E or S;
X 17 selected from R, K or Q;
X 18 selected from R, K or A;
X 20 selected from Q, K or H;
X 24 is selected from K or E;
X 34 selected from G or G-NH 2 ；
And wherein, position X 20 、X 24 Only one of them is K;
in a preferred embodiment of the present invention, in the amino acid sequence of the co-agonist polypeptide:
X 1 selected from Y, X 2 Selected from V, X 3 Selected from Q, X 12 Selected from R, X 15 Selected from E, X 16 Selected from E, X 17 Selected from R, X 18 Selected from R, X 20 Selected from Q, X 24 Selected from K, X 34 Is selected from G-NH 2 ；
Or, X 1 Selected from H, X 2 Selected from V, X 3 Selected from Q, X 12 Selected from R, X 15 Selected from E, X 16 Selected from E, X 17 Selected from R, X 18 Selected from R, X 20 Selected from Q, X 24 Selected from K, X 34 Is selected from G-NH 2 ；
Or, X 1 Selected from Y, X 2 Selected from V, X 3 Selected from Q, X 12 Selected from K, X 15 Selected from E, X 16 Selected from E, X 17 Selected from K, X 18 Selected from K, X 20 Selected from K, X 24 Selected from E, X 34 Is selected from G-NH 2 ；
Or, X 1 Selected from H, X 2 Selected from I, X 3 Selected from Q, X 12 Selected from R, X 15 Selected from E, X 16 Selected from E, X 17 Selected from R, X 18 Selected from R, X 20 Selected from Q, X 24 Selected from K, X 34 Is selected from G;
or, X 1 Selected from H, X 2 Selected from S, X 3 Selected from H, X 12 Selected from S, X 15 Selected from D, X 16 Selected from S, X 17 Selected from Q, X 18 Selected from A, X 20 Selected from H, X 24 Selected from K, X 34 Is selected from G.
In a preferred embodiment of the present invention, the derivative is linked to a fatty acid side chain through an epsilon amino group on the amino acid K residue in position 20 or 24 of the polypeptide, i.e., the epsilon amino group of K20 or K24 of the polypeptide is linked to a fatty acid side chain. Wherein the "K number" indicates the lysine (K) at the position indicated by the "number" of the co-agonist polypeptide sequence, the epsilon-amino group of which is linked to a side chain; for example, "K20" refers to a lysine at position 20 of the corresponding co-agonist polypeptide sequence and indicates attachment to the corresponding fatty acid side chain via the epsilon-amino group of the lysine.
In the present invention, the "-NH at the tail end of the co-agonist polypeptide sequence 2 "indicates that the hydroxyl group in the carboxyl group of the terminal amino acid is replaced with-NH at the terminal 2 ", i.e., modification of the COOH of the tail amino acid to CONH 2 . The specific structure is as follows:
as a preferred embodiment of the present invention, the fatty acid sideThe chain is selected from HOOC (CH) 2 ) n CO-γ-Glu-(AEEA) 2 And n is any integer from 14 to 22.
As a preferred embodiment of the present invention, the fatty acid side chain is selected from HOOC (CH) 2 ) 16 CO-γ-Glu-(AEEA) 2 -or HOOC (CH) 2 ) 18 CO-γ-Glu-(AEEA) 2 -。
According to IUPAC nomenclature, HOOC (CH) 2 ) 16 CO-γ-Glu-(AEEA) 2 -may be referred to as "[2- (2- [2- (2- [2- (2-) 4- (17-carboxyheptadecanoylamino) -4 (S) -carboxybutanoylamino]Ethoxy) ethoxy]Acetylamino) ethoxy]Ethoxy) acetyl group]”。
According to IUPAC nomenclature, HOOC (CH) 2 ) 18 CO-γ-Glu-(AEEA) 2 May be referred to as "[2- (2- [2- (2- [2- (2-) 4- (19-carboxynonadecaalkanoylamino) -4 (S) -carboxybutanoylamino group]Ethoxy) ethoxy]Acetylamino) ethoxy]Ethoxy) acetyl group]”。
As a specific embodiment of the present invention, the derivative of the present invention comprises a fatty acid side chain linked to the epsilon amino group of the lysine at position 20 or 24 of the polypeptide, preferably the fatty acid side chain is HOOC (CH) 2 ) 16 CO-γ-Glu-(AEEA) 2 -or HOOC (CH) 2 ) 18 CO-γ-Glu-(AEEA) 2 -。
As a preferred technical scheme, the invention provides a group of GLP-1 receptor and GCG receptor co-agonist polypeptide derivatives, and the general formula of the amino acid sequence of the polypeptide derivatives or pharmaceutically acceptable salts thereof is shown as the following formula:
X 1 X 2 X 3 GTFTSDYSX 12 YLX 15 X 16 X 17 X 18 AX 20 EFVX 24 WLLEGGPSSX 34 ，
the specific structure of the derivative is shown in table 1:
TABLE 1
The co-agonist polypeptide derivatives in the above tables are each formed by connecting a GLP-1 receptor and GCG receptor co-agonist polypeptide (in the table, the co-agonist polypeptide sequence) to a fatty acid side chain, wherein the side chain is connected to an epsilon-amino group of an amino acid K at a designated position of the polypeptide sequence.
The polypeptide derivative or the pharmaceutically acceptable salt thereof can be prepared by a chemical synthesis method, and also can be prepared by a mode of preparing recombinant engineering bacteria, fermenting, expressing, purifying and modifying.
In a second aspect, the present invention provides a pharmaceutical composition, comprising the polypeptide derivative of the first aspect or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition can be an injection preparation, a tablet, a capsule, syrup, a granule, a block, an emulsion or a compound preparation.
As a preferred embodiment of the present invention, the pharmaceutical composition of the present invention can be administered parenterally, such as subcutaneous injection, intradermal injection, intravenous injection, intramuscular injection, intraperitoneal injection, etc. Preferably, the pharmaceutical composition for parenteral administration is an injection preparation, which comprises the polypeptide derivative or the pharmaceutically acceptable salt thereof as an effective raw material and pharmaceutically acceptable auxiliary materials.
As a preferred technical scheme, the pharmaceutically acceptable auxiliary materials are selected from one or more of buffering agents, osmotic pressure regulators, preservatives, stabilizing agents, cosolvents, antioxidants, pH value regulators and bacteriostats. Preferably, the adjuvant of the composition is 0.1-10mg/mL of buffer, 5-40mg/mL of osmotic pressure regulator and 1-10mg/mL of preservative. Further, the amount of buffer is 0.1-10mg/mL, 0.5-5mg/mL, or 0.8-2mg/mL, such as 1mg/mL or 1.5mg/mL; the buffer is preferably disodium hydrogen phosphate. The amount of the osmotic pressure regulator is 5-40mg/mL, 8-30mg/mL or 10-20mg/mL, such as 14mg/mL or 17mg/mL; the osmotic pressure regulator is preferably propylene glycol or glycerol, more preferably propylene glycol. The amount of the preservative is 1-10mg/mL, 1-8mg/mL, or 1-6mg/mL, such as 2mg/mL or 5mg/mL; the preservative is preferably phenol or m-cresol, more preferably phenol.
As a preferred technical scheme, the pharmaceutical composition of the invention can be orally administered, such as directly orally taken, incorporated into drinking water or food, or by intragastric administration. The pharmaceutical composition for oral delivery is a solid composition, the polypeptide derivative or the pharmaceutically acceptable salt thereof according to the first aspect is used as an effective raw material, and the components such as a penetration enhancer are added, so that the absorption of the oral drug in a human body depends on the absorption promoting effect of the penetration enhancer. The pharmaceutical composition comprises any one of the co-agonist polypeptide derivatives or pharmaceutically acceptable salts thereof and N- (8- (2-hydroxybenzoyl) amino) caprylate described in table 1, wherein the amount of the co-agonist polypeptide derivative or pharmaceutically acceptable salt thereof is 5-20mg, the amount of the N- (8- (2-hydroxybenzoyl) amino) caprylate is preferably sodium N- (8- (2-hydroxybenzoyl) amino) caprylate (SNAC), and the amount of the SNAC is 200-400mg, and the oral formulation is preferably an oral tablet. Preferably, the amount of said co-agonist polypeptide derivative or pharmaceutically acceptable salt thereof is 5mg, 10mg, 15mg or 20mg; the amount of SNAC is 250-350mg, more preferably 250mg, 280mg, 300mg, 320mg or 350mg.
As a preferred technical solution of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient selected from one or more of a binder, a filler, a disintegrant, a lubricant and a glidant. Preferably, the excipients of the composition are 0.1-10% w/w of binder, 5-40% w/w of filler and 0.1-10% w/w of lubricant. Further, the amount of the binder is 0.1-10% w/w,0.2-4% w/w,0.5-3% w/w, such as 1% w/w or 2% w/w; the binder is preferably povidone. The amount of said filler is 5-40% w/w,10-30% w/w or 5-25% w/w, as 10.9% w/w, 18% w/w, 19.5% w/w, or 20.5% w/w; the filler is preferably microcrystalline cellulose. The amount of the lubricant is 0.1-10% w/w,0.5-5% w/w or 1-3.5% w/w, such as 1% w/w; the lubricant is preferably magnesium stearate.
In a third aspect, the present invention provides the use of a polypeptide derivative according to the first aspect or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect, in the manufacture of a medicament for the treatment of diabetes.
In a fourth aspect, the present invention provides a polypeptide derivative or a pharmaceutically acceptable salt thereof according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in the preparation of a medicament for weight loss.
Compared with the prior art, the technical scheme provided by the embodiment of the invention has the following advantages:
the GLP-1 receptor and GCG receptor co-agonist polypeptide derivative provided by the invention has balanced GLP-1 receptor and GCG receptor agonistic activity, has prolonged action time, can be used for treating insulin-dependent diabetes, and has remarkable excellent weight loss effect.
Detailed Description
In order that the above objects, features and advantages of the present invention may be more clearly understood, a solution of the present invention will be further described below. It should be noted that the embodiments of the present invention and features of the embodiments may be combined with each other without conflict.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those described herein; it is to be understood that the embodiments described in this specification are only some embodiments of the invention, and not all embodiments.
Example 1: preparation of GLP-1 receptor and GCG receptor co-agonist polypeptide
This example provides various GLP-1 receptor and GCG receptor co-agonist polypeptide derivatives and methods for their preparation, where this example is a chemical synthesis method, and the preparation method is as follows (taking C-010 as an example):
synthesis of C-010 crude peptide
1.1 swelling deprotection of the resin
Weighing Fmoc-Linker-MBHA resin with the loading capacity of about 0.3, putting the Fmoc-Linker-MBHA resin into a reaction column, swelling the resin with DCM for 30min, removing the solution, washing the resin with DMF for 2 times, and removing the solution. Adding a proper amount of 20% piperidine/DMF solution, reacting for 5min under nitrogen blowing, pumping out the solution, adding a proper amount of 20% piperidine/DMF solution, reacting for 10min under nitrogen blowing, and then washing the resin for 6 times by using a proper amount of DMF to obtain the resin with Fmoc protecting groups removed.
1.2 peptide ligation reactions
Weighing a certain amount of Fmoc-Gly-OH protected amino acid and a condensing agent TBTU, adding into a reaction column, adding a proper amount of DMF solvent, adding a certain amount of alkali DIEA, reacting at room temperature for 1-2h under the blowing of nitrogen, and monitoring the reaction process by using a Kaiser reagent (ninhydrin color development method). After the reaction was complete, the resin was washed 3 times with DMF. The deprotection step is then repeated: adding an appropriate amount of 20% piperidine/DMF solution, reacting for 5min under nitrogen blowing, removing the solution, adding an appropriate amount of 20% piperidine/DMF solution, reacting for 10min under nitrogen blowing, washing the resin with an appropriate amount of DMF for 6 times, and sequentially coupling from the C end to the N end according to the sequence. Wherein the protected amino acid used for attaching the side chain is Fmoc-Lys (dde) -OH and the last protected amino acid is Boc-His (Trt) -OH.
1.3 modification of the side chain
After all the backbone protected amino acids were coupled, add 2% hydrazine hydrate/DMF solution to remove the side chain dde protecting group of Lys, and then wash the resin 6-8 times with DMF. Fmoc-AEEA-OH, fmoc-AEEA-OH, fmoc-Glu-OTBU and C20diacid-Otbu are coupled in sequence according to a main chain coupling mode.
1.4 cleavage and drying of the polypeptide
The certain ratio of TFA to EDT to thioanisole to phenol to H 2 O = 88. Slowly adding the synthesized crude peptide resin into the precooled lysate, and oscillating or stirring the crude peptide resin to react for 2 hours at the temperature of about 26 ℃. The amount of lysis solution required for 1g of peptide resin was 8mL, or was adjusted appropriately.
And (3) carrying out suction filtration on the obtained lysate to obtain a clear solution, slowly adding the clear solution into precooled anhydrous ether, stirring, standing for 20min, centrifuging by using a centrifuge to obtain a white solid, centrifuging and washing by using normal-temperature ether for 4 times, and drying to obtain white powder crude peptide.
Purification of C-010
2.1 separation
Eluting the crude peptide with chromatography conditions of
Column (30mm 250mm), mobile phase 1:0.05M ammonium acetate (pH adjusted to about 8.0 with ammonia), mobile phase 2: and (3) acetonitrile. The elution gradient was a change in acetonitrile from 31% to 38% over 25 minutes, resulting in a sample with a purity greater than 95%.
2.2 spin-steaming Freeze-drying
And removing acetonitrile from the obtained C-010 solution by using a rotary evaporator, and freeze-drying by using a freeze dryer to obtain white solid powder.
The other end being-NH 2 The preparation method of the derivative of (4) is the same as that of C-010; while the tail is a normal amino acid and the non-tail is-NH 2 In step 1.1, wang resin (wang resin) was selected instead of Fmoc-Linker-MBHA resin, and the rest of the procedure was the same as in this example.
Example 2: in vitro GLP-1 receptor binding activity assay
Selecting HEK293/Luc/GLP1R cells with good culture state, discarding culture solution in the bottle, washing with PBS buffer solution for 1 time, adding 0.05% Trypsin digestive juice for digestion for 3 minutes, adding DMEM basal medium to terminate digestion, and centrifuging to collect cells. DMEM blank medium was used to adjust the cell density to 8.0X 10 5 one/mL, 50. Mu.L/well in 96-well cell culture plates, at 37 ℃ and 5% CO 2 Incubated under conditions overnight.
The in vitro GLP-1 receptor binding activity of the co-agonist polypeptide derivative is detected by a Fire-Lumi luciferase assay kit: preparing a determination culture solution, and diluting a sample to 320nM by using the determination culture solution step by step, wherein the single dilution multiple does not exceed 10 times; then, 5-fold serial dilutions were performed in 96-well plates for 8 gradients, with 2 duplicate wells for each dilution.
Removing the cultured cell culture plate from the incubator, adding diluted assay medium to the cell plate at 50. Mu.L/well, and subjecting to 37 ℃ and 5% CO 2 Incubate for 6h under conditions. The sample plate was removed from the incubator and allowed to stand at room temperature. Adding 100ul Fire-Lumi detection solution, reacting for 5min, shaking for 10s, and detecting fluorescence intensity.
The test data is processed by adopting a four-parameter regression calculation method, and the EC50 value of the sample to be detected can be calculated. The results are shown in table 2:
TABLE 2
| Sample (I) | Somazutide | C-003 | C-010 | C-011 | C-012 | B-012 |
| EC50 | 1.3 | 5.9 | 4.8 | 67.1 | 40.3 | 16.2 |
As is clear from the results shown in Table 2, all of C-003, C-010, C-011, C-012 and B-012 of the present invention have GLP-1 receptor-binding ability and GLP-1 receptor agonist activity. Among them, GLP-1 receptor agonists with C-003 and C-010 have the best activity, similar to thaumatin.
Example 3: in vitro GCG receptor binding Activity assay
Selecting HEK293/GCGR/Ga15 cells with good culture state, discarding culture solution in the bottle, and using PBS buffer solutionWashing 1 time, adding TRYPSIN digestion solution 0.05% (v/v), adding DMEM basic culture solution to stop digestion, and centrifuging to collect cells. DMEM blank medium was used to adjust the cell density to 8X 10 5 one/mL, 5. Mu.L/well was seeded in 96-well cell culture plates.
Assay medium (DMEM medium supplemented with 0.5nM IBMX) was prepared and samples were diluted stepwise with assay medium to 100nM with a single dilution factor of no more than 10-fold, followed by 4-fold serial dilutions in 96-well plates for 8 gradients, with 2 duplicate wells per dilution.
Taking out the cultured cell culture plate from the incubator, adding the diluted determination culture solution into the cell plate, and incubating for 30min at 37 ℃; adding cAMP-d2 working solution, 5 mu L of cAMP Eu-Cryptate antibody working solution into each hole, covering a sealing plate membrane on a 96-well plate, and incubating for 60min at room temperature; after the incubation was complete, the plate-sealing membrane was removed and detection was performed in FRET mode (665nm, 620nm) using an HTRF reader.
The test data is processed by adopting a four-parameter regression calculation method, and the EC50 value of the sample to be tested can be calculated. The results are shown in table 3:
TABLE 3
| Sample (I) | Somazutide | C-003 | C-010 | C-011 | C-012 | B-012 |
| EC50 | - | 5.2 | 4.8 | 36.8 | 8.38 | 8.7 |
The results in Table 3 show that while Somalutide has no binding activity to GCG receptor, C-003, C-010, C-011, C-012 and B-012 of the present invention all have the ability to bind to GCG receptor and have GCG receptor agonist activity. Among them, GCG receptor agonist activity with C-003 and C-010 is most preferred.
Example 4: study on weight loss effect and food intake of DIO mice
(1) Experimental materials: c57BL/6J (DIO) mice
Selecting male C57 mice 16-17 weeks old and fed with healthy SPF (specific pathogen free) high-fat feed (60% fat), weighing 35-40g, and adaptively feeding for 14-17 days; randomly grouping mice according to body weight, wherein each group comprises 6 mice, and is divided into a model control group, a somalutide group, a C-003 group, a C-010 group and a B-012 group;
(2) The experimental method comprises the following steps:
a. the administration mode comprises the following steps:
the medicine is taken once a Day, the administration route is abdominal subcutaneous injection, the administration time period of the medicine is fixed during the administration, the first Day of formal administration is recorded as Day1, and the contents of specific administration dosage and the like are shown in table 4:
TABLE 4
b. Detection indexes are as follows:
weight: detecting the body weight at each administration;
food intake: detecting the food intake after each administration;
(3) Results of the experiment
The test results of this example are shown in tables 5 and 6:
TABLE 5
TABLE 6
The experimental results show that the thaumatin, the C-003, the C-010 and the B-012 have weight reducing effects in different degrees, wherein the C-010 has a weight reducing effect which is remarkably superior to that of the thaumatin, and the weight reducing effect in a mouse reaches 22.7 percent in 7 days, but the thaumatin is only 16.1 percent and is 1.4 times that of the thaumatin.
Example 5: research on OGTT (one glass transition temperature) blood glucose reducing effect of C57BL/6J mice
(1) Experimental materials:
healthy male mice are selected and adaptively bred for 7 days, the mice are randomly grouped according to the weight, 10 mice are in each group, and the mice are divided into a model control group, a C-003 group and a B-012 group, wherein:
model control group: comprises 10 mice, glucose (2 g/Kg) is orally taken, and blank solvent is injected into the abdomen and subcutaneous part;
group C-003: comprises 10 mice, glucose (2 g/Kg) is orally taken, and the drug is injected into the abdomen and the skin;
group B-012: 10 mice were included and glucose (2 g/Kg) was administered orally and the drug was injected subcutaneously into the abdomen.
(2) Experimental methods
a. The administration mode comprises the following steps:
the mice of each experimental group identified above were dosed according to the specific dosing schedule shown in table 7:
TABLE 7
b. Blood sugar value detection:
the test animals were fasted without water deprivation before blood glucose testing, in the afternoon of the same day, and the fasted body weight (to calculate the dose and glucose dose) was obtained 16h after fasting in the morning of the following day. Blood glucose was measured 0h before dosing, and then a blank solvent or drug solution was injected subcutaneously. The animals were fed glucose (2 g/Kg) orally 3h after dosing, blood glucose was measured 15min, 30min, 60min and 120min after glucose was administered orally, and two glucose readings were taken by a glucometer. The mean of the two glucose readings was reported at each time point, the blood glucose change curve was plotted and the AUC area was calculated. The results are shown in Table 8:
TABLE 8
Note: "" means, p < 0.05 relative to model control; ". Indicates, p < 0.01 relative to model control.
According to the same method, a model control group, a C-010 group, a C-011 group and a C-012 group are respectively tested, and the results of the blood sugar reduction experiment are shown in a table 9:
TABLE 9
Note: "" means, p < 0.05 relative to model control; ". Indicates, p < 0.01 relative to model control.
Experimental results show that the C-003, C-010 and B-012 groups of the invention have obvious hypoglycemic effects, wherein the C-010 has the most obvious effect and the hypoglycemic effect is obviously superior to that of other control groups. It was also confirmed in comparative studies that it has a hypoglycemic effect comparable to that of somaglutide.
It is noted that, herein, relational terms such as "first" and "second," and the like, may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrases "comprising a," "8230," "8230," or "comprising" does not exclude the presence of additional like elements in a process, method, article, or apparatus that comprises the element.
The above description is merely illustrative of particular embodiments of the invention that enable those skilled in the art to understand or practice the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (15)
1. A GLP-1 receptor and GCG receptor co-agonist polypeptide derivative or a pharmaceutically acceptable salt thereof, wherein the derivative is a GLP-1 and GCG receptor co-agonist polypeptide acylated and connected with a fatty acid side chain, and the amino acid sequence of the polypeptide is shown as the following formula:
X 1 X 2 X 3 GTFTSDYSX 12 YLX 15 X 16 X 17 X 18 AX 20 EFVX 24 WLLEGGPSSX 34
wherein:
X 1 selected from Y or H;
X 2 selected from I, V or S;
X 3 is selected from Q or H;
X 12 selected from R, K or S;
X 15 selected from E or D;
X 16 selected from E or S;
X 17 selected from R, K or Q;
X 18 selected from R, K or A;
X 20 selected from Q, K or H;
X 24 is selected from K or E;
X 34 selected from G or G-NH 2 ；
And wherein, position X 20 、X 24 Only one of which is K.
2. The polypeptide derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein:
X 1 selected from Y or H, X 2 Selected from V, X 3 Selected from Q, X 12 Selected from R, X 15 Selected from E, X 16 Selected from E, X 17 Selected from R, X 18 Selected from R, X 20 Selected from Q, X 24 Selected from K, X 34 Is selected from G-NH 2 ；
Or, X 1 Selected from Y, X 2 Selected from V, X 3 Selected from Q, X 12 Selected from K, X 15 Selected from E, X 16 Selected from E, X 17 Selected from K, X 18 Selected from K, X 20 Selected from K, X 24 Selected from E, X 34 Is selected from G-NH 2 ；
Or, X 1 Selected from H, X 2 Selected from I, X 3 Selected from Q, X 12 Selected from R, X 15 Selected from E, X 16 Selected from E, X 17 Selected from R, X 18 Selected from R, X 20 Selected from Q, X 24 Selected from K, X 34 Is selected from G;
or, X 1 Selected from H, X 2 Selected from S, X 3 Selected from H, X 12 Selected from S, X 15 Selected from D, X 16 Selected from S, X 17 Selected from Q, X 18 Selected from A, X 20 Selected from H, X 24 Selected from K, X 34 Is selected from G.
3. The polypeptide derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the derivative is linked to a fatty acid side chain through an epsilon amino group on the amino acid K residue in position 20 or 24 of the polypeptide.
4. The polypeptide derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the fatty acid side chain is selected from HOOC (CH) 2 ) n CO-γ-Glu-(AEEA) 2 And n is any integer from 14 to 22.
5. The polypeptide derivative or pharmaceutically acceptable salt thereof according to claim 4, wherein the fatty acid side chain is selected from HOOC (CH) 2 ) 16 CO-γ-Glu-(AEEA) 2 -or HOOC (CH) 2 ) 18 CO-γ-Glu-(AEEA) 2 -。
6. A pharmaceutical composition comprising the polypeptide derivative of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is an injection, a tablet, a capsule, a syrup, a granule, a block, an emulsion, or a combination.
8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is an injection formulation and the excipient is selected from the group consisting of a buffer, an osmotic pressure regulator, and a preservative.
9. The pharmaceutical composition of claim 8, wherein the buffering agent is disodium phosphate, the tonicity adjusting agent is propylene glycol, and the preservative is phenol.
10. The pharmaceutical composition of claim 9, wherein the disodium phosphate is present at a concentration of 0.1-10mg/mL, the propylene glycol is present at a concentration of 5-40mg/mL, and the phenol is present at a concentration of 1-10mg/mL.
11. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is an oral delivery solid formulation comprising the polypeptide derivative of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and N- (8- (2-hydroxybenzoyl) amino) caprylate.
12. The pharmaceutical composition according to claim 11, wherein the salt of N- (8- (2-hydroxybenzoyl) amino) caprylic acid is preferably SNAC.
13. The pharmaceutical composition of claim 12, wherein the co-agonist polypeptide derivative or pharmaceutically acceptable salt thereof is present in an amount of 5-20mg and the SNAC is present in an amount of 200-400mg.
14. The pharmaceutical composition of any one of claims 11-13, wherein the composition of the oral delivery solid formulation further comprises a binder, a filler, and a lubricant.
15. The pharmaceutical composition of claim 14, wherein the binder is povidone, the filler is microcrystalline cellulose, and the lubricant is magnesium stearate.
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