CN112724240A - Xenopus laevis glucagon-like peptide-1 analogue and application thereof - Google Patents
Xenopus laevis glucagon-like peptide-1 analogue and application thereof Download PDFInfo
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- CN112724240A CN112724240A CN202110187642.7A CN202110187642A CN112724240A CN 112724240 A CN112724240 A CN 112724240A CN 202110187642 A CN202110187642 A CN 202110187642A CN 112724240 A CN112724240 A CN 112724240A
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Abstract
The invention relates to a xenopus laevis GLP-1 analogue, a synthesis method and an application thereof, wherein the xenopus laevis GLP-1 analogue with higher hypoglycemic activity and longer pharmacological action time is obtained by carrying out structural modification on the side chain and the C terminal of the xenopus laevis GLP-1. The xenopus laevis GLP-1 analogue has obviously improved biological activity and has strong long-acting hypoglycemic and weight-losing effects.
Description
The invention relates to a divisional application, the application number of the original application is 2017111943239, the application date is 24/11 in 2017, and the invention name is Xenopus laevis GLP-1 analogue and the application thereof.
Technical Field
The invention relates to the field of biological medicines, in particular to a xenopus laevis glucagon-like peptide-1 analogue and application thereof.
Background
Diabetes Mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia caused by various causes such as heredity and environment. Due to relative or absolute insufficiency of insulin secretion; or insulin deficiency causes a series of metabolic disorders such as sugar, protein, fat, water and electrolytes. Persistent hyperglycemia is an essential feature. Prolonged illness can cause multiple system damage, leading to chronic complications of the eyes, kidneys, nerves, and organs such as the heart, cerebral vessels, lower limbs, etc. The world health organization first released a global report of diabetes on the year 2016, 6 months, showing a 3-fold increase in adult patients with diabetes worldwide in the last 40 years, with most living in developing countries. Reports show that the diabetes rate of Chinese adults is close to 10%. Diabetes is classified into type 1 diabetes and type 2 diabetes and gestational diabetes and other specific types of diabetes. More than 90% of patients with type 2 diabetes are found in research. The current methods for treating diabetes mainly comprise oral hypoglycemic drugs and insulin treatment, but the methods can generate toxic and side effects in long-term treatment.
The Glucagon-Like Peptide-1 (GLP-1) has the function of protecting beta cells, and the GLP-1 can act on the beta cells of the pancreatic islets, promote the transcription of insulin genes and the synthesis and secretion of insulin, stimulate the proliferation and differentiation of the beta cells of the pancreatic islets, inhibit the apoptosis of the beta cells of the pancreatic islets and increase the number of the beta cells of the pancreatic islets. In addition, GLP-1 can act on islet alpha cells to strongly inhibit the release of glucagon, and acts on islet delta cells to promote the secretion of somatostatin, and the somatostatin can be used as a paracrine hormone to participate in inhibiting the secretion of glucagon. Research proves that GLP-1 can obviously improve the blood sugar condition of a type 2 diabetes animal model or a patient through a plurality of mechanisms, wherein the functions of promoting the regeneration and the repair of islet beta cells and increasing the number of the islet beta cells are particularly obvious, and a very good prospect is provided for the treatment of type 2 diabetes. However, native GLP-1 has a limitation that it has a very short half-life and is degraded by dipeptidyl peptidase (DPP-IV) after 2-3 minutes of secretion, and even when GLP-1 is exogenously administered, it is also degraded by DPP-IV. In addition, endogenous GLP-1 is also rapidly filtered and metabolized by the kidney, and the in vivo half-life is only 2-3 min. Therefore, there is a need to find new GLP-1 receptor agonists that have similar biological activity to GLP-1 but long-lasting effect in vivo.
The blood sugar reducing activity of the xenopus laevis GLP-1(XenGLP-1) is superior to that of natural GLP-1, and in addition, the special amino acid sequence of the xenopus laevis GLP-1 makes the xenopus laevis GLP-1 have better in vivo stability and is an excellent lead polypeptide. The fatty acid compounds in the natural product have stronger serum protein binding rate, and the drugs combined by the serum albumin and the free drugs generate balance in vivo and are slowly released to realize long-acting effect. Meanwhile, the serum albumin combined drug is not easy to be filtered by glomeruli, so that the filtering metabolism of the kidney can be avoided. Therefore, a fatty acid compound taking long-chain fatty acid as a parent nucleus is designed, and is connected with a XenGLP-1 peptide chain through glutamic acid (gamma-Glu) or short-chain polyethylene glycol-glutamic acid (PEG-gamma-Glu).
Disclosure of Invention
The invention relates to a xenopus laevis glucagon-like peptide-1 (XenGLP-1) analogue, the structure of which has the following form:
His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Xaa2-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Xaa3-Gly-Xaa4-Xaa5(SEQ.ID NO:1)
wherein:
Xaa1ala, Gly or Aib;
Xaa2lys (fat acid analog) or Lys;
Xaa3lys (fat acid analog) or Lys;
Xaa4lys (fat acid analog) or Lys;
Xaa5:Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2，Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-OH，Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-OH, -OH or-NH2；
Provided that the sequence is not
His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-NH2,His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-OH，His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2，His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-OH，His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2Or His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-OH；
And pharmaceutically acceptable salts, solvates, chelates or non-covalent complexes of the analogs, prodrugs based on the analogs, or any mixture of the above analogs.
Wherein Lys (fat acid analog) is selected from
Here: n is 12-20.
Wherein the most preferred Lys (fat acid analog) structure is
The amino acid sequence of the preferred XenGLP-1 analogue is shown in SEQ.ID NO. 2-31.
The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above-mentioned XenGLP-1 analogues or pharmaceutically acceptable salts, solvates, chelates or non-covalent complexes thereof, prodrugs based on the analogue, or any mixture of analogues in the above forms, and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further provides application of the XenGLP-1 analogue or the pharmaceutically acceptable salt or the pharmaceutical composition thereof in medicines.
The XenGLP-1 analogue takes liraglutide and semaglutide as reference and HEK highly expressing GLP-1 receptor is utilized in-vitro experiment293Cell model, evaluated for its in vitro receptor agonistic activity. And the in vitro stability of the composition is evaluated by warm compress of human plasma. In vivo experiments, diabetic mice and obese mice are used as experimental models to identify the long-acting blood sugar reducing and weight losing effects. In vitro and in vivo experimental results show that the XenGLP-1 analogue provided by the invention has extremely high in vitro stability, and is obviously superior to liraglutide and semaglutide in the aspects of blood sugar reducing action time and weight reducing effect.
The invention has the advantages that:
the xenopus laevis GLP-1(XenGLP-1) analogue has the advantages that the stability in vivo is obviously superior to that of natural GLP-1 due to the special amino acid sequence, the XenGLP-1 analogue obtained by further modifying fatty acid has the advantages that the time of the action of reducing blood sugar in vivo and the function of losing weight are obviously superior to those of liraglutide and semaglutide which take a GLP-1 peptide chain as a main body, and the xenopus laevis GLP-1 analogue can be widely applied to the treatment of diabetes and obesity.
Drawings
Having thus described the invention in general terms, the following drawings are provided to illustrate specific embodiments of the invention. Wherein:
FIG. 1 shows a degradation diagram of an in vitro plasma stability experiment of a XenGLP-1 analog;
FIG. 2 shows a blood glucose-time profile for a long-acting hypoglycemic test with XenGLP-1 analogues;
figure 3 shows a graph of the body weight change of the XenGLP-1 analogue in the body weight reduction experiment.
Detailed Description
The following abbreviations are used throughout the specification:
DMF: dimethylformamide; DCM: dichloromethane; fmoc: n-9-fluorenylmethyloxycarbonyl; DIC: n, N' -diisopropylcarbodiimide; HOBT: 1-hydroxy-benzotriazole; TFA: trifluoroacetic acid; EDT (electro-thermal transfer coating): dimercaptoethane; HPLC: high performance liquid chromatography; ESI-MS: electrospray mass spectrometry; LC-MS: (ii) liquid mass spectrometry; gly: glycine; ser: serine; ala: alanine; thr: threonine; val: valine; ile: isoleucine; leu: leucine; tyr: tyrosine; phe: phenylalanine; his: (ii) histidine; pro: (ii) proline; asp: aspartic acid; met: (ii) methionine; glu: glutamic acid; trp: tryptophan; lys: lysine; arg: arginine; asn: asparagine; gln: (ii) glutamine; cys: cysteine.
The present invention is illustrated by the following examples, which are not to be construed as limiting the invention in any way.
Examples 1
(1) Swelling of the resin
0.262g (0.1mmol) of Rink Amide MBHA resin loaded at 0.382mmol/g was weighed into a 25mL reactor, the resin was washed 1 time with 7mL of DCM and methanol alternately, 2 times with 7mL of DCM, then the resin was swollen with 7mL of DCM for 1h, and finally 3 times with 7mL of DMF.
(2) Removal of Fmoc protecting group of resin
Transferring the swelled resin into a polypeptide synthesizer, adding 7mL of 20% piperidine/DMF, reacting at room temperature for 5min, filtering the deprotected solution, washing the resin once with 7mL of DMF, adding 7mL of 20% piperidine/DMF, deprotecting and washing the resin for 15min, and finally washing the resin 4 times with 7mL of DMF, wherein each time lasts for 1.5min, so as to obtain the Rink resin for removing the Fmoc protecting group.
(3) Synthesis of Fmoc-Lys-Rink amide-MBHA Resin
Fmoc-Lys (Boc) -OH (0.4mmol) was weighed, dissolved in 3mL of 10% DMF/DMSO, 2mL of DIC/HOBt (0.4mmol/0.44mmol) was added, and after stirring for 30min, the activated amino acid was added to the reactor, the reaction was shaken at room temperature for 2h, the reaction solution was filtered off, and the resin was washed 4 times with 7mL of DMF.
(5) Elongation of peptide chain
And repeating the deprotection and coupling steps according to the sequence of the peptide chain to connect corresponding amino acids in sequence until the synthesis of the peptide chain is finished. Wherein the Lys of the fatty acidification site is Fmoc-Lys (Dde) -OH with special side chain protecting group, and the N-terminal His is Boc-His (Boc) -OH.
(6) Lys site-directed lipolysis modification
And after the peptide chain synthesis is finished, adding 7mL of 2% hydrazine hydrate/DMF (dimethyl formamide) to selectively remove the Dde protecting group of the Lys of the fatty acidification site, adding 0.4mmol of Fmoc-Glu-OtBu, 0.4mmol of DIC and 0.44mmol of HOBt after the Dde protecting group is removed, and carrying out oscillation reaction for 2 hours. Then, Fmoc was removed by the same method, 0.4mmol of small palmitic acid molecule, 0.4mmol of DIC and 0.44mmol of HOBt were added and condensation was carried out for 2 hours, and the reaction solution was filtered off and the resin was washed 4 times with 7mL of DMF.
(7) Cleavage of polypeptides
Transferring the obtained resin connected with the polypeptide into a round-bottom bottle, cutting the resin by using 5mL of cutting agent Reagent R (TFA/thioanisole/phenol/EDT, 90:5:3:2, V/V), reacting for 2h in an oil bath at constant temperature of 30 ℃, pouring cutting liquid into 40mL of ethyl acetate, washing a crude product by using 15mL of ethyl acetate after freezing and centrifuging for 3 times, and finally drying by using nitrogen gas to obtain the crude peptide.
(8) Purification of polypeptides
Dissolving the crude target polypeptide product in water at a concentration of 10mg/mL, filtering with a 0.25-micrometer microporous membrane, and purifying with Shimadzu preparative reversed-phase HPLC system. The chromatographic conditions were C18 reverse phase preparative columns (250 mm. times.20 mm, 12 μm); mobile phase A: 0.1% TFA/water (V/V), mobile phase B: ethanol (V/V); the flow rate is 15 mL/min; the detection wavelength was 214 nm. Eluting by linear gradient (55% B-90% B/30min), collecting target peak, and freeze-drying to obtain pure product. The theoretical relative molecular mass is 3838.3. ESI-MS M/z calu [ M +3H ]]3+1290.4,[M+4H]4+968.1；found[M+3H]3+1290.2,[M+4H]4+968.0。
Examples 2 to 19
According to the method described in the embodiment 1, the xenopus laevis glucagon-like peptide-1 (xenoglp-1) analogue of the embodiment 2-30 is obtained by synthesis according to the corresponding sequence and side chain, and the respective molecular weight is confirmed by ESI-MS.
Example 2
The theoretical relative molecular mass is 3838.3. ESI-MS M/z calu [ M +3H ]]3+1290.4,[M+4H]4+968.1；found[M+3H]3+1290.6,[M+4H]4+968.5。
Example 3
The theoretical relative molecular mass is 3838.3. ESI-MS M/z calu [ M +3H ]]3+1290.4,[M+4H]4+968.1；found[M+3H]3+1290.4,[M+4H]4+968.3。
Example 4
The theoretical relative molecular mass is 3896.4. ESI-MS M/z calu [ M +3H ]]3+1299.8,[M+4H]4+975.1；found[M+3H]3+1300.2,[M+4H]4+975.6。
Example 5
The theoretical relative molecular mass is 3896.4. ESI-MS M/z calu [ M +3H ]]3+1299.8,[M+4H]4+975.1；found[M+3H]3+1300.0,[M+4H]4+975.3。
Example 6
The theoretical relative molecular mass is 3896.4. ESI-MS M/z calu [ M +3H ]]3+1299.8,[M+4H]4+975.1；found[M+3H]3+1299.9,[M+4H]4+975.1。
Example 7
The theoretical relative molecular mass is 4646.2. ESI-MS M/z calu [ M +4H ]]4+1162.6,[M+5H]5+930.2；found[M+4H]4+1162.9,[M+5H]5+930.4。
Example 8
The theoretical relative molecular mass is 4646.2. ESI-MS M/z calu [ M +4H ]]4+1162.6,[M+5H]5+930.2；found[M+4H]4+1162.5,[M+5H]5+930.2。
Example 9
The theoretical relative molecular mass is 4646.2. ESI-MS M/z calu [ M +4H ]]4+1162.6,[M+5H]5+930.2；found[M+4H]4+1162.7,[M+5H]5+930.7。
Example 10
The theoretical relative molecular mass is 4674.2. ESI-MS M/z calu [ M +4H ]]4+1169.6,[M+5H]5+935.8；found[M+4H]4+1169.9,[M+5H]5+936.1。
Example 11
The theoretical relative molecular mass is 4674.2. ESI-MS M/z calu [ M +4H ]]4+1169.6,[M+5H]5+935.8；found[M+4H]4+1170.2,[M+5H]5+936.3。
Example 12
The theoretical relative molecular mass is 4674.2. ESI-MS M/z calu [ M +4H ]]4+1169.6,[M+5H]5+935.8；found[M+4H]4+1169.4,[M+5H]5+935.7。
Example 13
The theoretical relative molecular mass is 5318.1. ESI-MS M/z calu [ M +4H ]]4+1330.5[M+5H]5+1064.6；found[M+4H]4+1330.9,[M+5H]5+1064.8。
Example 14
The theoretical relative molecular mass is 5318.1. ESI-MS M/z calu [ M +4H ]]4+1330.5[M+5H]5+1064.6；found[M+4H]4+1330.5,[M+5H]5+1064.7。
Example 15
The theoretical relative molecular mass is 5318.1. ESI-MS M/z calu [ M +4H ]]4+1330.5[M+5H]5+1064.6；found[M+4H]4+1330.7,[M+5H]5+1064.6。
Example 16
The theoretical relative molecular mass is 5346.2. ESI-MS M/z calu [ M +4H ]]4+1337.6,[M+5H]5+1070.2；found[M+4H]4+1337.9,[M+5H]5+1070.5。
Example 17
The theoretical relative molecular mass is 5346.2. ESI-MS M/z calu [ M +4H ]]4+1337.6,[M+5H]5+1070.2；found[M+4H]4+1337.5,[M+5H]5+1070.3。
Example 18
The theoretical relative molecular mass is 5346.2. ESI-MS M/z calu [ M +4H ]]4+1337.6,[M+5H]5+1070.2；found[M+4H]4+1337.5,[M+5H]5+1070.3。
Example 19
The theoretical relative molecular mass is 4158.6. ESI-MS M/z calu [ M +4H ]]4+1040.6,[M+5H]5+832.7；found[M+4H]4+1040.9,[M+5H]5+832.8。
Example 20
The theoretical relative molecular mass is 4158.6. ESI-MS M/z calu [ M +4H ]]4+1040.6,[M+5H]5+832.7；found[M+4H]4+1040.7,[M+5H]5+832.9。
Example 21
The theoretical relative molecular mass is 4936.5. ESI-MS M/z calu [ M +4H ]]4+1235.1,[M+5H]5+988.3；found[M+4H]4+1235.7,[M+5H]5+988.6。
Example 22
The theoretical relative molecular mass is 4936.5. ESI-MS M/z calu [ M +4H ]]4+1235.1,[M+5H]5+988.3；found[M+4H]4+1235.1,[M+5H]5+988.4。
Example 23
The theoretical relative molecular mass is 5608.4. ESI-MS M/z calu [ M +4H ]]4+1403.1,[M+5H]5+1122.7；found[M+4H]4+1403.5,[M+5H]5+1122.9。
Example 24
The theoretical relative molecular mass is 5608.4. ESI-MS M/z calu [ M +4H ]]4+1403.1,[M+5H]5+1122.7；found[M+4H]4+1403.2,[M+5H]5+1122.7。
Example 25
The theoretical relative molecular mass is 4216.7. ESI-MS M/z calu [ M +4H ]]4+1055.2,[M+5H]5+844.3；found[M+4H]4+1055.6,[M+5H]5+844.6。
Example 26
The theoretical relative molecular mass is 4216.7. ESI-MS M/z calu [ M +4H ]]4+1055.2,[M+5H]5+844.3；found[M+4H]4+1055.2,[M+5H]5+844.4。
Example 27
The theoretical relative molecular mass is 4994.5. ESI-MS M/z calu [ M +4H ]]4+1249.6,[M+5H]5+999.9；found[M+4H]4+1249.9,[M+5H]5+1000.3。
Example 28
The theoretical relative molecular mass is 4994.5. ESI-MS M/z calu [ M +4H ]]4+1249.6,[M+5H]5+999.9；found[M+4H]4+1250.1,[M+5H]5+1000.2。
Example 29
The theoretical relative molecular mass is 5666.4. ESI-MS M/z calu [ M +4H ]]4+1417.6,[M+5H]5+1134.3；found[M+4H]4+1417.8,[M+5H]5+1134.6。
Example 30
The theoretical relative molecular mass is 5666.4. ESI-MS M/z calu [ M +4H ]]4+1417.6,[M+5H]5+1134.3；found[M+4H]4+1418.0,[M+5H]5+1134.9。
Example 31
In vitro GLP-1 receptor agonism assay
Cloning cDNA encoding human GLP-1 receptor to a vector pcDNA3.0, and transfecting HEK293Obtaining HEK stably expressing the human GLP-1 receptor293A cell. The cells were cultured in DMEM-31053 medium, and HEK was added 2h before experiment293Cells were resuspended in growth medium and seeded in 96-well plates. Dissolving liraglutide, semaglutide and SEQ. ID NO:2-31 in DMSO, diluting according to a concentration gradient of 1pM-1000nM, adding to a 96-well plate, incubating at room temperature for 20 minutes, measuring the amount of cAMP produced using a cAMP kit in an Envision2104 microplate reader, analyzing the data, and calculating the EC of the compound50The value is obtained.
As shown in Table 1, the receptor agonistic activity of all the XenGLP-1 analogues is better than that of liraglutide and semagllutide, the receptor agonistic activity of the XenGLP-1 analogue with the modified C terminal is higher than that of the XenGLP-1 analogue without the modified C terminal, the length of the side chain fatty chain of the XenGLP-1 analogue is inversely proportional to the receptor agonistic activity of the XenGLP-1 analogue, and the introduction of the short chain PEG segment in the side chain of the fatty chain has no influence on the receptor agonistic activity of the XenGLP-1 analogue.
TABLE 1 in vitro Activity of Liraglutide, semaglutide and XenGLP-1 analogs
Example 32
In vitro plasma stability assay for XenGLP-1 analogs
Blood is taken from rat eyeballs, the blood is put into a centrifuge tube containing heparin, centrifugation is carried out for 10 minutes at 3000rpm, supernatant blood plasma is taken as incubation blood plasma, and response signals of the compounds are detected by LC-MS. Mixing 100uL of liraglutide, semaglutide and SEQ ID NO. 2-31 solution with 100uL of plasma, vortex mixing, placing in a water bath at 37 ℃, incubating for 96 hours, taking 10uL at time points of 0, 12, 24, 48, 72 and 96 hours, adding 20uL of acetonitrile for precipitation, centrifuging at 14000rpm, taking supernatant fluid into LC-MS, calculating peak areas of all time points, making an attenuation curve, and calculating half-life. As shown in fig. 1, the half-lives of liraglutide and semaglutide were 16.3 and 45.9h, respectively, whereas the half-lives of all XenGLP-1 analogues were all above 60h, with the longest half-life exceeding 96 h.
Example 33
In vivo acute hypoglycemic Activity of XenGLP-1 analogs
Simultaneous administration of glucose, test compound: male db/db mice of 10 weeks of age were randomly divided into groups of 6 mice each. Water was given alone and fasted overnight. One group was intraperitoneally injected with 18mmol of glucose solution (concentration: 20%) and physiological saline per kg of mouse body weight; the other groups were injected intraperitoneally with 18mmol of glucose solution and 25nmol of liraglutide, semaglutide and SEQ ID NO. 2, SEQ ID NO. 8, SEQ ID NO. 14, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30 solution (10. mu. mol/L) per kg of mouse body weight. Blood glucose levels were measured with a glucometer at 0, 15, 30, 45, 60 min. As shown in Table 1, the blood sugar reducing activity of the modified XenGLP-1 analogue is obviously superior to that of liraglutide and semaglutide, so that the application prospect is good, and the blood sugar reducing activity of the analogue is not influenced by the fatty acid modification.
TABLE 1 hypoglycemic Effect of Liraglutide, semaglutide and XenGLP-1 analogues
Example 34
Long-acting hypoglycemic test of XenGLP-1 analogue
8 week old db/db diabetes model mice are adaptively raised for one week, and are randomly grouped into six mice each group after the blood glucose value of the mice measured by a glucometer is higher than 20 mmol/L. The test samples were divided into positive control group liraglutide and semaglutide (25nmol/kg), negative control group normal saline, compound groups of SEQ ID NO:2, SEQ ID NO:8, SEQ ID NO:14, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, and SEQ ID NO:30(25 nmol/kg). Mice were allowed free water, diet, and compound administration for 0h, and blood glucose was measured with a glucometer at 0, 6, 12, 24, 48, and 72h, and a time-blood glucose curve was generated. As shown in figure 2, the long-acting hypoglycemic activity of the XenGLP-1 analogue is obviously better than that of liraglutide and semaglutide, and the hypoglycemic time of most of the XenGLP-1 analogues exceeds 72 h.
Example 35
Weight loss assay for XenGLP-1 analogs
9 weeks old db/db diabetes model mice, adaptive breeding for one week, random grouping, each group of 6. Mice were given positive control liraglutide and semaglutide (25nmol/kg) daily, negative control saline, administration group was given SEQ.ID NO:2, SEQ.ID NO:8, SEQ.ID NO:14, SEQ.ID NO:20, SEQ.ID NO:22, SEQ.ID NO:24, SEQ.ID NO:26, SEQ.ID NO:28, SEQ.ID NO:30(25nmol/kg) daily, treatment cycle was 40 days, and body weight of mice was measured every 10 days. As shown in figure 3, the XenGLP-1 analogues can obviously reduce the weight of mice, and the weight-reducing effect of the analogues is obviously better than that of positive controls liraglutide and semaglutide, which indicates that the XenGLP-1 analogues have good medicinal prospects for treating diabetes and losing weight.
Sequence listing
<110> university of Jiangsu profession
<120> xenopus laevis glucagon-like peptide-1 analogues and application thereof
<160> 31
<170> SIPOSequenceListing 1.0
<210> 1
<211> 31
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 1
His Xaa Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Xaa Gly Xaa Xaa
20 25 30
<210> 2
<211> 30
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 2
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys
20 25 30
<210> 3
<211> 30
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 3
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys
20 25 30
<210> 4
<211> 30
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 4
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Xaa
20 25 30
<210> 5
<211> 30
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 5
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys
20 25 30
<210> 6
<211> 30
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 6
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys
20 25 30
<210> 7
<211> 30
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 7
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Xaa
20 25 30
<210> 8
<211> 39
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 8
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 9
<211> 39
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 9
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 10
<211> 39
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 10
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Xaa Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 11
<211> 39
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 11
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 12
<211> 39
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 12
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 13
<211> 39
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 13
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Xaa Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 14
<211> 44
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 14
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
35 40
<210> 15
<211> 44
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 15
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
35 40
<210> 16
<211> 44
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 16
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Xaa Pro Ser
20 25 30
Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
35 40
<210> 17
<211> 44
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 17
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
35 40
<210> 18
<211> 44
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 18
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
35 40
<210> 19
<211> 44
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 19
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Xaa Pro Ser
20 25 30
Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
35 40
<210> 20
<211> 30
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 20
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys
20 25 30
<210> 21
<211> 30
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 21
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys
20 25 30
<210> 22
<211> 39
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 22
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 23
<211> 39
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 23
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 24
<211> 44
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 24
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
35 40
<210> 25
<211> 44
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 25
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
35 40
<210> 26
<211> 30
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 26
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys
20 25 30
<210> 27
<211> 30
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 27
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys
20 25 30
<210> 28
<211> 39
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 28
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 29
<211> 39
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 29
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 30
<211> 44
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 30
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
35 40
<210> 31
<211> 44
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 31
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
20 25 30
Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
35 40
Claims (8)
1. A xenopus laevis glucagon-like peptide-1 analog, characterized in that it has the sequence:
His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Xaa2-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Xaa3-Gly-Xaa4-Xaa5；
wherein:
Xaa1ala, Gly or Aib;
Xaa2lys (fat acid analog) or Lys;
Xaa3lys (fat acid analog) or Lys;
Xaa4lys (fat acid analog) or Lys;
Xaa5:Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2，Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-OH，Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-OH, -OH or-NH2；
And the sequence is not His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-NH2,His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-OH，His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2，His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-OH，His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2Or His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-OH。
2. The xenopus laevis glucagon-like peptide-1 analog of claim 1, wherein lys (fatty acid analog) is lys (f atty acid analog)
3. The xenopus laevis glucagon-like peptide-1 analog of claim 2, wherein n is 12-20.
4. The xenopus laevis glucagon-like peptide-1 analog of claim 1, wherein lys (fat acid analog) is of the formula one of:
5. the xenopus laevis glucagon-like peptide-1 analog of claim 1, wherein the sequence is one of the following:
6. a pharmaceutical composition comprising a xenopus glucagon-like peptide-1 analog of claim 1, or a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex thereof, a prodrug on the analog basis, or a mixture of any of the foregoing forms of the analog, and one or more pharmaceutically acceptable carriers, diluents or excipients.
7. Use of a xenopus laevis glucagon-like peptide-1 analog as described in claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 5 for the manufacture of a medicament.
8. The use according to claim 7, wherein the medicament is a medicament for the treatment of at least one of the following diseases: type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disease, stroke, inflammatory bowel syndrome, or dyspepsia.
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| CN201711194323.9A CN108359005A (en) | 2017-11-24 | 2017-11-24 | Africa xenopus GLP-1 analogs and application thereof |
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| CN110759991A (en) * | 2019-12-09 | 2020-02-07 | 江苏师范大学 | Gemfibrozil-xenopus laevis glucagon-like peptide-1 derivative and application thereof |
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| CN109762059B (en) * | 2019-03-28 | 2021-01-12 | 清紫生物科技（深圳）有限公司 | Novel glucagon analogue and application thereof |
| CN112608378B (en) * | 2020-12-09 | 2023-09-08 | 江苏师范大学 | GLP-1/cholecystokinin-1 receptor dual agonist and application thereof |
| KR20240118914A (en) | 2021-01-20 | 2024-08-05 | 바이킹 테라퓨틱스 인코포레이티드 | Compositions and methods for the treatment of metabolic and liver disorders |
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| CN110759991A (en) * | 2019-12-09 | 2020-02-07 | 江苏师范大学 | Gemfibrozil-xenopus laevis glucagon-like peptide-1 derivative and application thereof |
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