CN116712530B - Long-acting GLP-1/glucon/GIP receptor triple agonist and application thereof - Google Patents
Long-acting GLP-1/glucon/GIP receptor triple agonist and application thereof Download PDFInfo
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- CN116712530B CN116712530B CN202310845213.3A CN202310845213A CN116712530B CN 116712530 B CN116712530 B CN 116712530B CN 202310845213 A CN202310845213 A CN 202310845213A CN 116712530 B CN116712530 B CN 116712530B
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Abstract
The invention discloses a long-acting GLP-1/glucagon/GIP receptor triple agonist and application thereof, wherein the receptor triple agonist can act on a GLP-1 receptor, a glucagon receptor and a GIP receptor simultaneously, and can exert the activities of GLP-1, glucagon and GIP simultaneously; not only has the therapeutic effect of GLP-1 on diabetes, but also has the beneficial effects of glucopon on weight, energy metabolism and lipid metabolism, and also has the beneficial effects of GIP on glucose, lipid metabolism and appetite suppression, thereby generating synergistic effect on glucose, lipid and energy metabolism; the preparation method has greater potential in preparing medicaments for treating metabolic syndrome, such as diabetes, obesity, hypertension, nonalcoholic fatty liver disease, nonalcoholic fatty hepatitis, dyslipidemia and the like.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a long-acting GLP-1/glucopon/GIP receptor triple agonist and application thereof.
Background
Obesity and its related metabolic syndrome have become global public health problems, and the incidence and progression of many metabolic syndromes such as type 2 diabetes (T2 DM), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), dyslipidemia are closely related to obesity. Studies have shown that clinically 80-90% of T2DM patients are associated with overweight or obesity. The current medicines for treating obesity have limited curative effects, and many medicines for treating obesity have obvious side effects. Among the current drugs for treating T2DM, only glucagon-like peptide (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT 2) inhibitors have a better weight control effect (j.med.chem., 2018,61,5580-5593).
Glucagon-like peptide-1 (GLP-1) is a glucose-dependent hypoglycemic polypeptide hormone secreted by small intestine L cells, and plays a hypoglycemic role after being specifically combined with GLP-1 receptor. The main advantage of GLP-1 is the glucose-dependent incretin secretion effect, avoiding the risk of hypoglycemia often present in diabetes treatment. In addition to regulating blood glucose, GLP-1 can also prevent pancreatic beta cell degeneration, stimulate beta cell proliferation and differentiation, and can improve diabetes progression from the source. In addition, GLP-1 also has the effects of inhibiting gastric acid secretion, delaying gastric emptying, inhibiting appetite and the like, and has partial weight reduction effect. Several long-acting GLP-1 drugs, such as liraglutide, semaglutide, are currently marketed. Although GLP-1 drugs have safe hypoglycemic effect, if better weight loss effect is required, the administration dosage is generally increased, and large-dose administration of GLP-1 drugs is easy to produce gastrointestinal side effects and poor tolerance, so that the treatment window is narrower. Thus, there remains a need for therapeutic agents that are more safely tolerated, and that are effective in reducing body weight and controlling blood glucose.
Glucagon (glucon) is a hormone secreted by islet alpha cells. Acts on liver in stress state such as organism cold and hunger, and decomposes glycogen in liver to increase blood sugar. In addition to its glycemic effect, glucopon has effects of promoting lipolysis, fat oxidation, fever, etc. (diabetes, 2017,60,1851-1861), and long-term administration can exhibit weight-reducing effects by increasing energy metabolism, but the beneficial effects of glucopon on energy metabolism have not been utilized because of its inherent glycemic effect.
Glucose-dependent insulinotropic polypeptide (GIP) is a 42 amino acid gastrointestinal regulatory peptide, and GLP-1 is an incretin that plays a key physiological role in the metabolism of blood glucose in the body. GIP exerts its physiological activity in vivo through the action of GIP receptors distributed in islet beta cells, adipose tissue and central nervous system. Similar to GLP-1, GIP can stimulate insulin secretion by islet beta cells to lower blood glucose, and can protect islet beta cells to control glucose metabolism in vivo. In addition, GIP also agonizes GIP receptors in adipose tissues to promote fat metabolism, and GIP also has an appetite-suppressing effect.
The receptors GLP-1 receptor, the glucagon receptor and the GIP receptor corresponding to GLP-1, glucagon and GIP belong to GPCR receptor families, and have similar protein structures and binding mechanisms, so that multiple agonists aiming at the three receptors can be designed. The multiple agonists of the three receptors can act on triple agonists of GLP-1 receptor, glucagon receptor and GIP receptor simultaneously, and can exert the activities of GLP-1, glucagon and GIP simultaneously. GLP-1 can reduce blood sugar and suppress appetite; glucopon can break down fat, reduce weight, raise blood sugar, but can be counteracted by the hypoglycemic activity of GLP-1; GIP mainly stimulates insulin secretion. The three activities of the triple agonists of the GLP-1 receptor, the glucoon receptor and the GIP receptor are matched with each other, and a feedback mechanism is formed according to the concentration of blood sugar, so that the blood sugar can be controlled, the fat can be decomposed, and the weight can be reduced. For the treatment of diabetes, obesity, GLP-1/glucon/GIP receptor triple agonists have significant advantages over the GLP-1 analogues alone.
Disclosure of Invention
The invention provides a long-acting GLP-1/glucogen/GIP receptor triple agonist and application thereof, wherein the agonist can act on a GLP-1 receptor, a glucogen receptor and a GIP receptor simultaneously, and can exert the activities of GLP-1, glucogen and GIP simultaneously; not only has the therapeutic effect of GLP-1 on diabetes, but also has the beneficial effects of glucopon on weight, energy metabolism and lipid metabolism, and also has the beneficial effects of GIP on glucose, lipid metabolism and appetite suppression, thereby generating synergistic effect on glucose, lipid and energy metabolism; the preparation method has greater potential in preparing medicaments for treating metabolic syndrome, such as diabetes, obesity, hypertension, nonalcoholic fatty liver disease, nonalcoholic fatty hepatitis, dyslipidemia and the like.
In order to achieve the above object, the present invention has the following technical scheme:
a long-acting GLP-1/glucopon/GIP receptor triple agonist, wherein the amino acid sequence general formula of the GLP-1/glucopon/GIP receptor triple agonist is as follows:
His-Xaa 1 -His-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Ile-Tyr-Leu-Glu-Xaa 2 -Xaa 3 -Xaa 4 -Ala-Aib-Gl u-Phe-Val-Gln-Trp-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 ，
wherein: xaa 1 Selected from D-Ala, gly or Aib; xaa 2 Selected from Lys with modified side chains; xaa 3 Selected from Lys or Gln; xaa 4 Selected from Tyr or Ala;
the side chain modified Lys is selected from
Wherein: n is a natural number, and n is more than or equal to 16 and less than or equal to 20.
Preferably, n is 16, 18 or 20.
Preferably, the sequence structure of the receptor triple agonist is selected from any one of the amino acid sequences shown in SEQ ID NOs 1-12:
SEQ ID NO:1
SEQ ID NO:2
SEQ ID NO:3
SEQ ID NO:4
SEQ ID NO:5
SEQ ID NO:6
SEQ ID NO:7
SEQ ID NO:8
SEQ ID NO:9
SEQ ID NO:10
SEQ ID NO:11
SEQ ID NO:12
the invention also provides pharmaceutically acceptable salts of the long-acting GLP-1/glucopon/GIP receptor triple agonists.
Further, the pharmaceutically acceptable salt is a salt of a long acting GLP-1/glucopon/GIP receptor triple agonist with one of the following compounds; the following compounds include hydrochloric acid, formic acid, acetic acid, pyruvic acid, butyric acid, caproic acid, benzenesulfonic acid, pamoic acid, benzoic acid, salicylic acid, lauric acid, cinnamic acid, propionic acid, dodecylsulfuric acid, citric acid, ascorbic acid, wine stearic acid, oxalic acid, lactic acid, succinic acid, malonic acid, maleic acid, fumaric acid, aspartic acid, sulfosalicylic acid.
The invention also provides a medicament prepared from the long-acting GLP-1/glucopon/GIP receptor triple agonist, wherein the medicament comprises any one of a tablet, a capsule, syrup, tincture, inhalant, spray, injection, film, patch, powder, granule, emulsion, suppository or compound preparation.
The invention also provides a pharmaceutical composition prepared from the long-acting GLP-1/glucopon/GIP receptor triple agonist, wherein the pharmaceutical composition comprises the long-acting GLP-1/glucopon/GIP receptor triple agonist and a pharmaceutically acceptable carrier or diluent; or the pharmaceutical composition comprises a pharmaceutically acceptable salt, a pharmaceutically acceptable carrier or a diluent of the long-acting GLP-1/glucopon/GIP receptor triple agonist.
The invention also provides the application of the long-acting GLP-1/glucopon/GIP receptor triple agonist or the pharmaceutically acceptable salt of the long-acting GLP-1/glucopon/GIP receptor triple agonist or the medicament or the pharmaceutical composition in preparing medicaments for treating metabolic diseases or symptoms; the metabolic disease or disorder includes diabetes, obesity, hypertension, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis or dyslipidemia.
The compound prepared by the invention has strong agonistic activity to GLP-1 receptor and strong agonistic activity to glucogon receptor, but has weak agonistic activity to GIP receptor, realizes better hypoglycemic and weight-reducing effects, and provides a new thought for preparing multiple agonists.
Compared with the prior art, the invention has the beneficial technical effects that:
(1) The GLP-1/glucon/GIP receptor triple agonist provided by the invention has the remarkable weight reduction and weight gain prevention effects while reducing blood sugar more effectively, and can be used for regulating lipid metabolism better;
(2) The GLP-1/glucopon/GIP receptor triple agonist has a unique N-terminal 6-10 bit sequence structure (YTNDV) and a unique in-vitro GLP-1 receptor, glucopon receptor and GIP receptor agonistic activity proportion, thereby bringing about remarkably improved weight loss and lipid metabolism regulation effects and having unexpected beneficial effects;
(3) Compared with the reported GLP-1/glucagon/GIP receptor triple agonist, the GLP-1/glucagon/GIP receptor triple agonist has similar GLP-1 receptor and glucagon receptor agon activity and obviously weaker GIP receptor agon activity, but the weight reduction, lipid metabolism regulation and glucose reduction activity are obviously improved, has more potential in the aspect of treating metabolic diseases, and provides a new thought for the drug development of the multiple agonist;
(4) The receptor triple agonists provided by the invention are chemically stable and have pharmacokinetic profiles that support at least once weekly dosing; the receptor triple agonist provided by the invention has better treatment effect on metabolic diseases such as T2DM, obesity, dyslipidemia and the like than the existing medicines on the market. Therefore, the receptor triple agonist provided by the invention is suitable for being used as an active ingredient of medicaments for treating metabolic diseases, such as diabetes, obesity, nonalcoholic steatohepatitis, dyslipidemia and the like.
Drawings
FIG. 1 shows the percentage change in body weight of each subject of the invention over 21 days of prolonged DIO mice administration.
Detailed Description
The present invention will be described in detail below with reference to the drawings and examples.
Unless defined otherwise herein, scientific and technical terms used in this specification shall have the meanings commonly understood by one of ordinary skill in the art. Generally, the terms and methods used in connection with chemistry, molecular biology, cell biology, pharmacology, according to the invention, are well known and commonly used in the art.
All combinations of the various elements disclosed herein are within the scope of the invention. Furthermore, the scope of the invention should not be limited by the specific disclosure provided below.
Further, the amino acids mentioned in the present invention may be abbreviated as follows according to the naming convention of IUPAC-IUB:
alanine (Ala, a); arginine (Arg, R); asparagine (Asn, N); aspartic acid (Asp, D); cysteine (Cys, C); glutamic acid (Glu, E); glutamine (Gln, Q); glycine (Gly, G); histidine (His, H); isoleucine (Ile, I); leucine (Leu, L); lysine (Lys, K); methionine (Met, M); phenylalanine (Phe, F); proline (Pro, P); serine (Ser, S); threonine (Thr, T); tryptophan (Trp, W); tyrosine (Tyr, Y); valine (Val, V).
Further, unless explicitly indicated, all amino acid residues in the polypeptides of the invention are preferably in the L configuration.
Further, "-NH on the C-terminus of the sequence 2 "part indicates an amide group (-CONH) at the C-terminus 2 )。
Further, in addition to natural amino acids, unnatural amino acids, alpha-aminoisobutyric acid (Aib) are used in the sequences of the invention.
Furthermore, the polypeptide compound can be synthesized by a polypeptide solid-phase synthesis method or can be produced by a genetic engineering technology.
The following specific embodiments are provided in order to illustrate the present invention in more detail, but the aspects of the present invention are not limited thereto.
Example 1
Synthesis of polypeptide Compound of SEQ ID NO. 1
(1) Swelling of the resin
0.338g (0.1 mmol equivalent) of Rink Amide MBHA resin with a loading of 0.296mmol/g was weighed into a 25mL reactor, the resin was alternately washed 1 time with 7mL of DCM and methanol, 2 times with 7mL of DCM, then the resin was swollen with 7mL of DCM for 1h, and finally the resin was washed 3 times with 7mL of DMF.
(2) Removal of Fmoc protecting groups from resin
Transferring the swelled resin into a PSI-200 polypeptide synthesizer, adding 7mL of 20% piperidine/DMF (v/v) for reaction at room temperature for 5min, filtering off the deprotection solution, washing the resin once by 7mL of DMF, adding 7mL of 20% piperidine/DMF (v/v) for reaction with the resin for 15min, and washing the resin 4 times by 7mL of DMF for 1.5min each time to obtain the Rink resin without Fmoc protecting groups.
(3) Synthesis of Fmoc-Ser-Rink amide-MBHAresin
Fmoc-Ser (tBu) -OH (0.4 mmol) was weighed, dissolved in 3mL 10% DMF/DMSO (v/v), 2mL DIC/HOBt (0.4 mmol/0.44 mmol) condensing agent was added, pre-activated for 30min, the activated amino acid was added to the reactor, the reaction was allowed to react for 2h with shaking at room temperature, the reaction solution was filtered off, the resin was washed 4 times with 7mL DMF, and the Kaiser reagent was used to check if the reaction coupling was complete, if not, 2 times.
(4) Extension of peptide chain
And (3) according to the sequence of the peptide chain, repeating the deprotection and coupling steps to sequentially connect corresponding amino acids until the peptide chain is synthesized.
(5) Modification of Lys side chains
After the peptide chain synthesis is completed, 7mL of 2% hydrazine hydrate/DMF (v/v) is added to selectively remove Dde protecting group of 16-position Lys, and 0.4mmol of Boc-Lys (Fmoc) -OH,0.4mmol of DIC and 0.44mmol of HOBt are added after the Dde protecting group is removed to perform oscillation reaction for 2h. Then, after Fmoc protecting group was removed by the same method as above, boc-Lys (Fmoc) -OH,0.4mmol DIC and 0.44mmol HOBt were added and the reaction was performed with shaking for 2 hours. Then, after Fmoc protecting groups were removed by the same method as described above, 0.4mmol of Fmoc-Glu-OtBu,0.4mmol of DIC and 0.44mmol of HOBt were added, followed by a shock condensation reaction for 2 hours. After removal of Fmoc protecting groups, 0.4mmol of mono-tert-butyl eicosadioate, 0.4mmol of DIC and 0.44mmol of HOBt were added for condensation for 2h, and after completion of the reaction the resin was washed 4 times with 7mL of DMF.
(6) Cleavage of polypeptides
The obtained resin connected with the polypeptide is transferred into a round bottom bottle, 5mL of a cutting agent Reagent R (TFA/benzyl sulfide/phenol/EDT, 90:5:3:2, V/V) is used for cutting the resin, the resin is reacted for 2 hours in an oil bath at the constant temperature of 30 ℃, the cutting fluid is poured into 40mL of glacial ethyl ether, the crude product is washed 3 times by 15mL of glacial ethyl ether after refrigerated centrifugation, and finally the crude peptide is obtained by drying with nitrogen.
(7) Purification of polypeptides
Dissolving the target polypeptide crude product in water, filtering with 0.25 μm microporous membrane, and purifying with island jin preparation type reversed phase HPLC system. Chromatographic conditions were C18 reverse phase preparation column (250 mm. Times.20 mm,12 μm); mobile phase a:0.1% TFA/water (V/V), mobile phase B: methanol (V/V); the flow rate is 8mL/min; the detection wavelength was 214nm. Eluting with linear gradient (20-70% B/30 min), collecting target peak, removing methanol, lyophilizing to obtain pure product 0.17g with purity greater than 98%, and determining molecular weight of target polypeptide by MS. The theoretical relative molecular mass is 4863.5.ESI-MS M/z calculated [ M+3H] 3+ 1622.2,[M+4H] 4+ 1216.9; observed value [ M+3H] 3+ 1622.2,[M+4H] 4+ 1216.6。
Example 2
Synthesis of polypeptide compound of SEQ ID No. 2
The synthesis method is the same as that of example 1, and the target peak is collected and freeze-dried to obtain 0.15g of pure productThe molecular weight of the target polypeptide was confirmed by MS with a degree of higher than 98%. The theoretical relative molecular mass is 4955.6.ESI-MS M/z calculated [ M+3H] 3+ 1652.9,[M+4H] 4+ 1239.9; observed value [ M+3H] 3+ 1652.5,[M+4H] 4+ 1239.9。
Example 3
Synthesis of polypeptide compound of SEQ ID No. 3
The synthesis method is the same as that of example 1, 0.16g of the target peak is collected and freeze-dried to obtain a pure product, the purity is more than 98%, and the molecular weight of the target polypeptide is confirmed by MS. The theoretical relative molecular mass is 4955.6.ESI-MS M/z calculated [ M+3H] 3+ 1652.9,[M+4H] 4+ 1239.9; observed value [ M+3H] 3+ 1652.5,[M+4H] 4+ 1239.7。
Example 4
Synthesis of polypeptide compound of SEQ ID No. 4
The synthesis was carried out as in example 1, except that the modification of the Lys side chain was carried out by changing mono-tert-butyl eicosanoate to mono-tert-butyl octadecanedioate. And collecting target peaks, freeze-drying to obtain 0.14g of pure product with purity of more than 98%, and confirming the molecular weight of target polypeptide by MS. The theoretical relative molecular mass is 4835.4.ESI-MS M/z calculated [ M+3H] 3+ 1612.8,[M+4H] 4+ 1209.8; observed value [ M+3H] 3+ 1612.6,[M+4H] 4+ 1209.7。
Example 5
Synthesis of polypeptide compound of SEQ ID No. 5
The synthesis was carried out as in example 1, except that the modification of the Lys side chain was carried out with mono-tert-butyl eicosadioateThe ester is converted into the mono-tert-butyl octadecanedioate. Collecting target peak, freeze-drying to obtain 0.15g of pure product with purity greater than 98%, and determining molecular weight of target polypeptide by MS. The theoretical relative molecular mass is 4927.5.ESI-MS M/z calculated [ M+3H] 3+ 1643.5,[M+4H] 4+ 1232.9; observed value [ M+3H] 3+ 1643.4,[M+4H] 4+ 1232.7。
Example 6
Synthesis of polypeptide compound of SEQ ID No. 6
The synthesis was carried out as in example 1, except that the modification of the Lys side chain was carried out by changing mono-tert-butyl eicosanoate to mono-tert-butyl octadecanedioate. Collecting target peak, freeze-drying to obtain 0.15g of pure product with purity greater than 98%, and determining molecular weight of target polypeptide by MS. The theoretical relative molecular mass is 4927.5.ESI-MS M/z calculated [ M+3H] 3+ 1643.5,[M+4H] 4+ 1232.9; observed value [ M+3H] 3+ 1643.4,[M+4H] 4+ 1232.8。
Example 7
Synthesis of polypeptide compound of SEQ ID No. 7
(1) Swelling of the resin
0.338g (0.1 mmol equivalent) of Rink Amide MBHA resin with a loading of 0.296mmol/g was weighed into a 25mL reactor, the resin was alternately washed 1 time with 7mL of DCM and methanol, 2 times with 7mL of DCM, then the resin was swollen with 7mL of DCM for 1h, and finally the resin was washed 3 times with 7mL of DMF.
(2) Removal of Fmoc protecting groups from resin
Transferring the swelled resin into a PSI-200 polypeptide synthesizer, adding 7mL of 20% piperidine/DMF (v/v) for reaction at room temperature for 5min, filtering off the deprotection solution, washing the resin once by 7mL of DMF, adding 7mL of 20% piperidine/DMF (v/v) for reaction with the resin for 15min, and washing the resin 4 times by 7mL of DMF for 1.5min each time to obtain the Rink resin without Fmoc protecting groups.
(3) Synthesis of Fmoc-Ser-Rink amide-MBHA Resin
Fmoc-Ser (Boc) -OH (0.4 mmol) was weighed, dissolved in 3mL 10% DMF/DMSO (v/v), 2mL DIC/HOBt (0.4 mmol/0.44 mmol) condensing agent was added, pre-activated for 30min, the activated amino acid was added to the reactor, the reaction was allowed to react for 2h with shaking at room temperature, the reaction solution was filtered off, the resin was washed 4 times with 7mL DMF, and the Kaiser reagent was used to check if the reaction coupling was complete, if not, 2 times.
(4) Extension of peptide chain
And (3) according to the sequence of the peptide chain, repeating the deprotection and coupling steps to sequentially connect corresponding amino acids until the peptide chain is synthesized.
(5) Modification of Lys side chains
After the peptide chain synthesis is completed, 7mL of 2% hydrazine hydrate/DMF (v/v) is added to selectively remove Dde protecting group of 16-position Lys, after the Dde protecting group is removed, 0.4mmol of Fmoc-AEEA-OH,0.4mmol of DIC and 0.44mmol of HOBt are added, and the oscillation condensation reaction is carried out for 2h. After removal of Fmoc protecting groups, 0.4mmol Fmoc-AEEA-OH,0.4mmol DIC and 0.44mmol HOBt were added again and the reaction was performed by shaking for 2h. After removal of Fmoc protecting groups, 0.4mmol Fmoc-Glu-OtBu,0.4mmol DIC and 0.44mmol HOBt were added and the reaction was performed by shaking for 2h. After removal of Fmoc protecting groups, 0.4mmol of mono-tert-butyl eicosadioate, 0.4mmol of DIC and 0.44mmol of HOBt were added for condensation for 2h, and after completion of the reaction the resin was washed 4 times with 7mL of DMF.
(6) Cleavage of polypeptides
The obtained resin connected with the polypeptide is transferred into a round bottom bottle, 5mL of a cutting agent Reagent R (TFA/benzyl sulfide/phenol/EDT, 90:5:3:2, V/V) is used for cutting the resin, the resin is reacted for 2 hours in an oil bath at the constant temperature of 30 ℃, the cutting fluid is poured into 40mL of glacial ethyl ether, the crude product is washed 3 times by 15mL of glacial ethyl ether after refrigerated centrifugation, and finally the crude peptide is obtained by drying with nitrogen.
(7) Purification of polypeptides
Dissolving the target polypeptide crude product in water, filtering with 0.25 μm microporous membrane, and purifying with island jin preparation type reversed phase HPLC system. Chromatographic condition C18 reverse phase preparation column(250 mm. Times.20 mm,12 μm); mobile phase a:0.1% TFA/water (V/V), mobile phase B: methanol (V/V); the flow rate is 8mL/min; the detection wavelength was 214nm. Eluting with linear gradient (20-70% B/30 min), collecting target peak, removing methanol, lyophilizing to obtain pure product 0.17g with purity greater than 98%, and determining molecular weight of target polypeptide by MS. The theoretical relative molecular mass is 4897.5.ESI-MS M/z calculated [ M+3H] 3+ 1633.5,[M+4H] 4+ 1225.4; observed value [ M+3H] 3+ 1633.4,[M+4H] 4+ 1225.3。
Example 8
Synthesis of polypeptide compound of SEQ ID No. 8
The synthesis method is the same as that of example 7, 0.16g of the target peak is collected and freeze-dried to obtain a pure product, the purity is more than 98%, and the molecular weight of the target polypeptide is confirmed by MS. The theoretical relative molecular mass is 4989.5.ESI-MS M/z calculated [ M+3H] 3+ 1664.2,[M+4H] 4+ 1248.4; observed value [ M+3H] 3+ 1664.1,[M+4H] 4+ 1248.2。
Example 9
Synthesis of polypeptide compound of SEQ ID No. 9
The synthesis method is the same as that of example 7, 0.16g of the target peak is collected and freeze-dried to obtain a pure product, the purity is more than 98%, and the molecular weight of the target polypeptide is confirmed by MS. The theoretical relative molecular mass is 4989.5.ESI-MS M/z calculated [ M+3H] 3+ 1664.2,[M+4H] 4+ 1248.4; observed value [ M+3H] 3+ 1664.1,[M+4H] 4+ 1248.1。
Example 10
Synthesis of polypeptide compound of SEQ ID No. 10
The synthesis was carried out as in example 7, except that the modification of the Lys side chain was carried out in such a way that mono-tert-butyl eicosanate was replaced by mono-tert-butyl octadecanedioate. Collecting target peak, freeze-drying to obtain 0.15g of pure product with purity greater than 98%, and determining molecular weight of target polypeptide by MS. The theoretical relative molecular mass is 4869.4.ESI-MS M/z calculated [ M+3H] 3+ 1624.1,[M+4H] 4+ 1218.4; observed value [ M+3H] 3+ 1624.1,[M+4H] 4+ 1218.1。
Example 11
Synthesis of polypeptide compound of SEQ ID NO. 11
The synthesis was carried out as in example 7, except that the modification of the Lys side chain was carried out in such a way that mono-tert-butyl eicosanate was replaced by mono-tert-butyl octadecanedioate. And collecting target peaks, freeze-drying to obtain 0.14g of pure product with purity of more than 98%, and confirming the molecular weight of target polypeptide by MS. The theoretical relative molecular mass is 4961.5.ESI-MS M/z calculated [ M+3H] 3+ 1654.8,[M+4H] 4+ 1241.4; observed value [ M+3H] 3+ 1654.7,[M+4H] 4+ 1241.2。
Example 12
Synthesis of polypeptide compound of SEQ ID NO 12
The synthesis was carried out as in example 7, except that the modification of the Lys side chain was carried out in such a way that mono-tert-butyl eicosanate was replaced by mono-tert-butyl octadecanedioate. And collecting target peaks, freeze-drying to obtain 0.17g of pure product, wherein the purity is more than 98%, and determining the molecular weight of target polypeptide by MS. The theoretical relative molecular mass is 4961.5.ESI-MS M/z calculated [ M+3H] 3+ 1654.8,[M+4H] 4+ 1241.4; observed value [ M+3H] 3+ 1654.7,[M+4H] 4+ 1241.3。
Example 13
Determination of agonistic Activity of polypeptide Compounds on GLP-1 receptor, glucoago receptor and GIP receptor
Agonism of the receptor by the polypeptide compounds is determined by a functional assay that measures cAMP response of HEK-293 cell lines stably expressing human GLP-1 receptor, glucoon receptor or GIP receptor. Cells stably expressing the three receptors were each split into T175 flasks and grown in medium overnight to near confluency, after which the medium was removed and the cells were washed with calcium and magnesium free PBS and then protease treated with Accutase enzyme. The detached cells were washed and resuspended in assay buffer (20mM HEPES,0.1%BSA,2mM IBMX,1 ×hbss) and cell density was determined and 25 μl aliquots were dispensed into wells of 96-well plates. For measurement, 25 μl of a solution of the test polypeptide compound in the assay buffer was added to the wells, followed by incubation at room temperature for 30 minutes. The cAMP content of cells was determined based on Homogeneous Time Resolved Fluorescence (HTRF) using the Cisbio kit. After addition of HTRF reagents diluted in lysis buffer (kit components), the plates were incubated for 1 hour, and then the fluorescence ratio at 665/620nm was measured. By detecting the concentration that caused 50% of activation of the maximal response (EC 50 ) To quantify the in vitro potency of the agonist.
The test data (nM) in the examples of this patent application are shown in Table 1 below, and although the test data is stated in terms of a number of significant digits, it should not be considered to indicate that the data has been determined to be exactly a significant digit.
Table 1: EC of polypeptide compounds to human GLP-1 receptor, glucagon receptor and GIP receptor 50 Value (expressed in nM)
As shown in Table 1, most polypeptide compounds have slightly stronger agonistic activity to GLP-1 receptor than natural GLP-1, most polypeptide compounds have about 4 times weaker agonistic activity to glucopon receptor than natural glucopon, and the GIP receptor agonistic activity of the polypeptide compounds of the invention is weaker than natural GIP (about 67-83 times weaker), which indicates that the polypeptide compounds of the invention have strong GLP-1 receptor agonistic activity, better glucopon receptor agonistic activity and weaker GIP receptor agonistic activity, have specific agonistic activity ratio to GLP-1 receptor, GIP receptor and glucopon receptor, and also accord with the characteristics of triple agonists described in the patent.
Example 14
Pharmacokinetic properties of polypeptide Compounds in rats
Rats were given 50nmol/kg of subcutaneous (s.c.) injection and blood samples were collected 0.25h, 0.5h, 1h, 2h, 4h, 8h, 16h, 24h, 36h and 48h after administration. After precipitation of the proteins using acetonitrile, plasma samples were analyzed by LC-MS. The pharmacokinetic parameters and half-life were calculated using WinnLin 5.2.1 (non-compartmental model) (Table 2).
Table 2: pharmacokinetic profile of polypeptide Compounds in rats
| Sample of | T 1/2 (h) | C max (ng/mL) |
| Semaglutide | 9.2 | 501 |
| SEQ ID NO:3 | 12.6 | 545 |
| SEQ ID NO:6 | 11.1 | 532 |
As the results in table 2 show, the in vivo half-life of the polypeptide compounds of the present invention is significantly prolonged over the once-a-week dosing of semaglutinide already on the market, demonstrating that the polypeptide compounds of the present invention have pharmacokinetic profiles that support at least once-a-week dosing.
Example 15
Influence of polypeptide Compounds on blood lipid and body weight in diet-induced obese (DIO) mice
Male C57BL/6J mice, weighing about 22g, were kept on the D12492 high fat diet of Research Diets for 18 weeks to make DIO mouse models. Before the start of the administration, the DIO mice were randomly grouped according to body weight, and 6 mice in each group were divided into 5 groups, namely, physiological saline group (blank control group), positive control group (semaglutide, tirzepatide and SAR441255 (GLP-1/glucon/GIP receptor triple agonist at clinical stage; cell metaolism, 2022,34,1-16)), and test sample group (SEQ ID NO: 3). Each group of mice was subcutaneously injected with normal saline (10 mg/kg), semaglutide (10 nmol/kg), tirzepatide (10 nmol/kg), SEQ ID NO:3 (10 nmol/kg), or SAR441255 (10 nmol/kg) twice daily for 21 days of the dosing period. The body weight changes of mice were recorded daily and Nuclear Magnetic Resonance (NMR) was used to measure body fat mass before and at the end of the experiment. At the end of the experiment, each group of mice was sacrificed and liver tissues were taken to measure liver Triglyceride (TG) and Total Cholesterol (TC) content. Blood serum was also collected and the serum glutamic-pyruvic transaminase (ALT), glutamic-oxaloacetic transaminase (AST), triglyceride (TG) and Total Cholesterol (TC) levels were measured.
Table 3: body weight and body fat changes in DIO mice over a 3 week dosing period
*** : p compared with the blank control group<0.001； ### : group ratio P to semaglutide, tirzepatide and SAR441255<0.001 (One-Way ANOVA, tukey post hoc test) the results are expressed as mean ± SD of 6 mice per group.
As shown in the results of fig. 1 and table 3, the polypeptide compound of the present invention, SEQ ID No. 3, was administered continuously in DIO mice for 3 weeks, the weight and body fat content of the mice could be significantly reduced, and the weight and body fat reducing effects of the polypeptide compound of the present invention were significantly stronger than those of the positive control semaglutide, tirzepatide and SAR441255. Notably, the GLP-1 receptor agonistic activity of SAR441255 is similar to native GLP-1, with the glucopon receptor agonistic activity being about 2-fold lower than native glucopon and the GIP receptor agonistic activity being about 2-fold lower than native GIP (Cell metaolism, 2022,34,1-16). From this, the GLP-1 receptor agonism and glucogon receptor agonism of SAR441255 are similar to those of SEQ ID NO. 3, but the GIP receptor agonism of SAR441255 is significantly stronger than that of SEQ ID NO. 3, and the polypeptide compound SEQ ID NO. 3 of the invention shows significantly better weight and body fat reducing activity than that of SAR441255.
Table 4: liver Triglyceride (TG) and Total Cholesterol (TC) levels 3 weeks after DIO mice treatment
| Sample (dose) | Total cholesterol (mg/g) | Triglyceride (mg/g) |
| Blank control (normal saline group) | 9.1±0.3 | 105.6±6.8 |
| Semaglutide(10nmol/kg) | 7.3±0.4 *** | 69.2±4.4 *** |
| Tirzepatide(10nmol/kg) | 6.8±0.2 *** | 60.3±3.5 *** |
| SAR441255(10nmol/kg) | 6.4±0.1 *** | 54.6±4.6 *** |
| SEQ ID NO:3(10nmol/kg) | 4.8±0.2 ***,### | 39.7±2.5 ***,### |
*** : p compared with the blank control group<0.001； ### : group ratio P to semaglutide, tirzepatide and SAR441255<0.001 (One-Way ANOVA, tukey post hoc test) the results are expressed as mean ± SD of 6 mice per group.
Table 5: serum glutamic pyruvic transaminase (ALT) and glutamic oxaloacetic transaminase (AST) levels after 3 weeks of DIO mice treatment
*** : p compared with the blank control group<0.001； ### : group ratio P to semaglutide, tirzepatide and SAR441255<0.001 (One-Way ANOVA, tukey post hoc test) the results are expressed as mean ± SD of 6 mice per group.
As shown in tables 4 and 5, the polypeptide compound prepared in the embodiment of the invention is continuously administered in DIO mice for 3 weeks, so that the liver triglyceride and total cholesterol content of the mice can be obviously reduced, the serum glutamic pyruvic transaminase and glutamic oxaloacetic transaminase content can be obviously reduced, and the effect of the polypeptide compound of the invention is obviously stronger than that of positive control medicines semaglutide, tirzepatide and SAR441255, which indicates that the polypeptide compound of the invention has good prospect for treating non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
Table 6: serum Triglyceride (TG) and Total Cholesterol (TC) levels 3 weeks after DIO mice treatment
| Sample (dose) | Total cholesterol (mmol/L) | Triglyceride (mmol/L) |
| Blank control (normal saline group) | 9.8±1.6 | 1.7±0.1 |
| Semaglutide(10nmol/kg) | 7.5±0.4 *** | 1.2±0.1 *** |
| Tirzepatide(10nmol/kg) | 6.9±0.5 *** | 1.1±0.2 *** |
| SAR441255(10nmol/kg) | 6.2±0.4 ** | 1.0±0.1 *** |
| SEQ ID NO:3(10nmol/kg) | 5.0±0.2 **,### | 0.4±0.1 ***,### |
*** : p compared with the blank control group<0.001； ### : group ratio P to semaglutide, tirzepatide and SAR441255<0.001 (One-Way ANOVA, tukey post hoc test) the results are expressed as mean ± SD of 6 mice per group.
As the results in table 6 show, the polypeptide compound of the present invention can significantly reduce serum triglyceride and total cholesterol content of mice by continuous administration in DIO mice for 3 weeks, and the effect of the polypeptide compound of the present invention for reducing serum lipid (triglyceride and cholesterol) content is significantly stronger than that of positive control semaglutide, tirzepatide and SAR441255.
Example 16
Effect of polypeptide Compounds on db/db mouse glycosylated hemoglobin (HbA 1 c) and blood glucose
Male db/db mice were randomly grouped, 6 per group. Physiological saline group (blank control group), positive control group (semaglutide, tirzepatide and SAR 441255) and test sample group (SEQ ID NO: 3), respectively. After one week of adaptive feeding, the tail bleed measures the initial HbA1c values and fasting blood glucose values before the start of the treatment. Each group of mice was subcutaneously injected with normal saline (10 mg/kg), semaglutide (10 nmol/kg), tirzepatide (10 nmol/kg), SEQ ID NO:3 (10 nmol/kg), or SAR441255 (10 nmol/kg) twice daily for a period of 35 days. The mice were fasted overnight after the end of treatment and blood was taken to measure the fasting blood glucose values and HbA1c (%).
Table 7: hbA1c (%) change in db/db mice over a 35 day dosing period
*** : p compared with the blank control group<0.001； ### : group ratio P to semaglutide, tirzepatide and SAR441255<0.001 (One-Way ANOVA, tukey post hoc test) the results are expressed as mean ± SD of 6 mice per group.
As shown in the results of Table 7, the polypeptide compound of the present invention was administered continuously in db/db mice for 35 days, the HbA1c value of the mice could be significantly reduced, and the HbA1c value of the mice of the polypeptide compound group of the present invention after treatment was significantly lower than those of the positive controls semaglutide, tirzepatide and SAR441255, indicating that the polypeptide compound of the present invention had a good glycemic control.
Table 8: fasting blood glucose changes in db/db mice over a 35 day dosing period
| Sample (dose) | Fasting blood glucose (%) |
| Blank control (normal saline group) | +5.2±0.5％ |
| Semaglutide(10nmol/kg) | -2.1±0.3％ *** |
| Tirzepatide(10nmol/kg) | -3.9±0.6％ *** |
| SAR441255(10nmol/kg) | -4.2±0.5％ *** |
| SEQ ID NO:3(10nmol/kg) | -9.3±0.2％ ***,### |
*** : p compared with the blank control group<0.001； ### : group ratio P to semaglutide, tirzepatide and SAR441255<0.001 (One-Way ANOVA, tukey post hoc test) the results are expressed as mean ± SD of 6 mice per group.
As shown in the results of Table 8, the polypeptide compound prepared in the embodiment of the invention can obviously reduce the fasting blood glucose value of db/db mice after being continuously administered in db/db mice for 35 days, which indicates that the polypeptide compound has excellent blood glucose control effect, and the blood glucose control effect of the polypeptide compound is obviously stronger than that of positive control medicines semaglutide, tirzepatide and SAR441255.
Claims (7)
1. A long-acting GLP-1/glucon/GIP receptor triple agonist, which is characterized in that the amino acid sequence of the receptor triple agonist is one of the following sequences:
SEQ ID NO:1
SEQ ID NO:2
SEQ ID NO:4
SEQ ID NO:5
SEQ ID NO:6
SEQ ID NO:7
SEQ ID NO:8
SEQ ID NO:9
SEQ ID NO:10
SEQ ID NO:11
SEQ ID NO:12
2. a class of pharmaceutically acceptable salts of the long acting GLP-1/glucon/GIP receptor triple agonists according to claim 1.
3. The pharmaceutically acceptable salt of a class of long acting GLP-1/glucopon/GIP receptor triple agonists according to claim 2, wherein the pharmaceutically acceptable salt is a salt of a long acting GLP-1/glucopon/GIP receptor triple agonist with one of the following compounds; the following compounds include hydrochloric acid, formic acid, acetic acid, pyruvic acid, butyric acid, caproic acid, benzenesulfonic acid, pamoic acid, benzoic acid, salicylic acid, lauric acid, cinnamic acid, propionic acid, dodecylsulfuric acid, citric acid, ascorbic acid, wine stearic acid, oxalic acid, lactic acid, succinic acid, malonic acid, maleic acid, fumaric acid, aspartic acid, sulfosalicylic acid.
4. A pharmaceutical formulation prepared from the long acting GLP-1/glucopon/GIP receptor triple agonist according to claim 1, wherein the pharmaceutical formulation comprises any one of a tablet, a capsule, a syrup, a tincture, an inhalant, a spray, an injection, a film, a patch, a powder, a granule, an emulsion, a suppository or a compound preparation.
5. A pharmaceutical composition prepared from a long-acting GLP-1/glucopon/GIP receptor triple agonist, wherein the pharmaceutical composition comprises a long-acting GLP-1/glucopon/GIP receptor triple agonist according to claim 1, and a pharmaceutically acceptable carrier or diluent; or the pharmaceutical composition comprises a pharmaceutically acceptable salt, a pharmaceutically acceptable carrier or diluent of a class of long acting GLP-1/glucopon/GIP receptor triple agonists according to any one of claims 2-3.
6. Use of a class of long acting GLP-1/glucopon/GIP receptor triple agonists according to claim 1 or a class of long acting GLP-1/glucopon/GIP receptor triple agonists according to any one of claims 2-3, a pharmaceutically acceptable salt thereof or a class of agents according to claim 4 or a pharmaceutical composition according to claim 5 for the manufacture of a medicament for the treatment of a metabolic disease or disorder.
7. The use according to claim 6, wherein the metabolic disease or disorder is diabetes, obesity, hypertension, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis or dyslipidemia.
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| WO2022090447A1 (en) * | 2020-10-30 | 2022-05-05 | Novo Nordisk A/S | Glp-1, gip and glucagon receptor triple agonists |
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