31results about How to "Overcoming the problem of short half-life" patented technology

The invention provides a glucagon-like peptide-1 mutant polypeptide, its preparation method and an application thereof. The mutant series polypeptide is formed by adding Cys series Exendin-4 (31-39) to the C terminal of the glucagon-like peptide-1 mutant. And the mutant series polypeptide folds itself to form a disulfide bond. The glucagon-like peptide-1 mutant polypeptide has an amino acid sequence as shown in SEQ ID NO 1, which is generated by point mutation to Cys occurring at the 9th Asp, 16th Gly or 27th Val of amino acid residues and the addition of Cys to the C terminal. The Exendin-4(31-39) has an amino acid sequence as shown in SEQ ID NO 5. The glucagon-like peptide-1 mutant series polypeptide is used for preparation of pharmaceutical compositions for treating diabetes and treating and / or preventing obesity.

The invention provides a GLP-1 dimer, a preparation method therefore and an application thereof. The GLP-1 dimer is formed by two GLP-1 monomers containing cysteine connected via a disulfide bond formed by cysteine. The general formula of the GLP-1 monomer containing cysteine is 7HAEX10T FTSX15V SSYLE X22X23AAKEFIX30W LX33KGR G37; wherein X10 is aglycine or cysteine, X15 is aspartic acid or cysteine, X22 is glycine or cysteine, X23 is leucine or cysteine, X30 is alanine or cysteine, X33 is valine or cysteine, and only one among X10, X15, X22, X23, X30 and X33 is cysteine. The GLP-1 dimer in the invention has an in vivo half-life of more than 8 to 96 hours, thus greatly facilitating clinical promotion and application.

The invention provides a glucagon-like peptide-1 mutant polypeptide, its preparation method and an application thereof. The mutant series polypeptide is formed by adding Cys series Exendin-4 (31-39) to the C terminal of the glucagon-like peptide-1 mutant. And the mutant series polypeptide folds itself to form a disulfide bond. The glucagon-like peptide-1 mutant polypeptide has an amino acid sequence as shown in SEQ ID NO 1, which is generated by point mutation to Cys occurring at the 9th Asp, 16th Gly or 27th Val of amino acid residues and the addition of Cys to the C terminal. The Exendin-4(31-39) has an amino acid sequence as shown in SEQ ID NO 5. The glucagon-like peptide-1 mutant series polypeptide is used for preparation of pharmaceutical compositions for treating diabetes and treating and / or preventing obesity.

The invention discloses GLP-1 analogs which have the following general formula I: 7HAEX10T FTSX15V SSYLE X22QAAK EFIX30W LX33KGR G37n1X1C n2X2, wherein X10 is glycine or cysteine, X15 is aspartic acid or cysteine, X22 is glycine or cysteine, X30 is alanine or cysteine, X33 is valine or cysteine, and at least one of X10, X15, X22, X30 and X33 is cysteine; n1X1 represents n X1s, n=3-30, and X1 is glycine, alanine or valine; n2X2 represents n X2s, n=3-30, and X2 is glycine, alanine or valine; and the two cysteines contained in the general formula I respectively form a disulfide bond. The GLP-1 analogs can effectively increase the blood half life of GLP-1, can overcome the actual state that the GLP-1 analogs can not be used clinically due to short half life, and has wide application prospects in the field of therapeutic drugs for diabetes and obesity. The invention also discloses a preparation method of the GLP-1 analogs and application thereof.

The invention discloses GLP-1 analogs, and a preparation method and an application thereof. The GLP-1 analogs have a following general formula A: <7>HAEX10TFTSDVSX18YLEX22QAX25KEFIX30WLX33KGRG<37>n1X1n2X2. With the GLP-1 analogs provided by the invention, GLP-1 blood half-life period can be effectively increased, such that a situation that GLP-1 cannot be clinically used due to short half-life period can be overcome. The GLP-1 analogs have application prospects in fields of medicines used for treating diabetes and obesity. The invention also discloses the preparation method and the application of the GLP-1 analogs.

The invention discloses a long-acting enterocrinin polypeptide analogue for treating type 2 diabetes and an application of the long-acting enterocrinin polypeptide analogue, and provides an analogue of GLP-1 (Glucagon-Like Peptide-1) with longer half-life period and an application of the analogue. The analogue of the GLP-1 has a following general formula A: HAEGTFTSDVSSYLEGQAAKEFIAWLX27KX29RX31n1YCZ. In the general formula A, X27 is valine or cysteine, X29 is glycine or cysteine, X31 is glycine or cysteine, and at least one of X27, X29 and X31 is cysteine; n1X1 represents n1Ys, n1 is equal to 1-10, and Y is glycine, alanine or valine; Z represents amino saturated fatty acid; and two cysteines contained in the general formula A both form disulfide bonds. The analogue of the GLP-1, provided by the invention, is capable of effectively increasing the blood half-life period of the GLP-1 and overcoming the current situation that the analogue can not be clinically used due to short half-life period, and has an application prospect in the fields of drugs for treating diabetes and adiposis.

The invention provides a long-acting glucagon-like peptide-1 analogue dimer. The long-acting glucagon-like peptide-1 analogue dimer is characterized in that the dimer is formed by two glucagon-like peptide-1 analogue monomers, the glucagon-like peptide analogue-1 monomer is shown as a general formula Z1HX1EX2TFTSDVSSYLEGQAAKEFIX3WLVKX4RG, wherein, Z1 is H, acetyl or trifluoroacetyl; X1 is Ala, Leu, Val, Gly, Ile; X2 is Gly, Cys; X3 is Ala, Cys; and X4 is Gly, Aib. The long-acting glucagon-like peptide-1 analogue dimer has long-acting hpyerglycemic effect, can increase the clinical medication compliance, is highly homologous with endogenous GLP-1(7-37), and can avoid the security risk.

The invention discloses a polypeptide compound, which contains Exendin-4 and a carrier polypeptide. The carrier polypeptide can effectively prolong blood half-life time of Exendin-4, overcomes the present situation that Exendin-4 cannot be used in clinical practice due to its short half-life time, and has an application prospect in the field of drugs for treating diabetes and obesity. The invention also discloses a preparation method of the polypeptide compound and an application thereof. In addition, the invention further discloses a pharmaceutical composition containing the polypeptide compound.

The present invention provides a glucagon-like peptide-2 analogue dimer, a preparation method and an application thereof, wherein two identical or different GLP-2 analogue monomers form a disulfide bond through cysteines on the monomers so as to prepare the dimer. The dimer preparation method comprises: adopting an Fmoc solid phase polypeptide synthesis method to synthesize a GLP-2 analogue monomer, and making the synthesized GLP-2 analogue monomers form a disulfide bond between the monomers. The application is an application of the GLP-2 analogue dimer in preparation of drugs for treatment of gastrointestinal related diseases. According to the present invention, with the GLP-2 analogue dimer formed from the GLP-2 analogue monomer, the problem of the short half-life of the GLP-2 is overcome, and the half-life of the GLP-2 analogue dimer can achieve more than 8-96 h in vivo, and is significantly prolonged compared with the half-life of the GLP-2 administered separately so as to substantially and easily achieve clinical promotion and application.

Provided are a GLP-1 analogue and uses thereof. The GLP-1 analogue has the following general formula: HAEGTFTSDVSSYLEGQAAKEFIAWLX27KX29RX31n1YCZ, wherein X27 is valine or cysteine, X29 is glycine or cysteine, X31 is glycine or cysteine, and at least one of X27, X29 and X31 is cysteine; n1Y represents n1 Ys, n1=1-10, and Y is glycine, alanine or valine; Z represents amino saturated fatty acid; and two cysteines contained in the general formula both form disulfide bonds. The GLP-1 analogue of the present invention can effectively increase the blood half-life period of GLP-1 and can be used for treating diabetes and adiposis.

The present invention provides a glucagon-like peptide-2 analogue dimer, a preparation method and an application thereof, wherein two identical or different GLP-2 analogue monomers form a disulfide bond through cysteines on the monomers so as to prepare the dimer. The dimer preparation method comprises: adopting an Fmoc solid phase polypeptide synthesis method to synthesize a GLP-2 analogue monomer, and making the synthesized GLP-2 analogue monomers form a disulfide bond between the monomers. The application is an application of the GLP-2 analogue dimer in preparation of drugs for treatment of gastrointestinal related diseases. According to the present invention, with the GLP-2 analogue dimer formed from the GLP-2 analogue monomer, the problem of the short half-life of the GLP-2 is overcome, and the half-life of the GLP-2 analogue dimer can achieve more than 8-96 h in vivo, and is significantly prolonged compared with the half-life of the GLP-2 administered separately so as to substantially and easily achieve clinical promotion and application.

GLP-1 analogues are disclosed. The general formula A of the GLP-1 analogues is shown as follows: <7>HAEGT FX<13>SDV SSY X<20>E X<22>QAA X<26>EFIAW LVKGR G<37>. In the general formula A, the X<13> is threonine or side-chain-modified lysine (K-nX), the X<20> is leucine or the side-chain-modified lysine (K-nX), the X<22> is glycine or the side-chain-modified lysine (K-nX), the X<26> is lysine (K-NH2) free of side chain modification or the side-chain-modified lysine (K-nX), just only one of the X<13>, the X<20>, the X<22> and the X<26> is the lysine (K-nX), the n is 4-10, and the X is the glycine, alanine or valine. The GLP-1 analogues effectively prolong the blood half-life period of GLP-1, overcome the current situation that the GLP-1 cannot be used in clinic due to the short half-life period of the GLP-1, and have an application prospect in the field of medicines treating diabetes and obesity. A preparing method of the GLP-1 analogues and applications of the GLP-1 analogues are also disclosed.

The invention discloses a polypeptide complex, which comprises GLP-1 (glucagon-like peptide-1) and a carrier polypeptide, wherein the carrier polypeptide can effectively prolong blood half life of GLP-1, thus the existing condition that GLP-1 cannot be clinically used due to short half life is overcome, and GLP-1 has better application prospects in the field of medicaments for treating diabetes and obesity. The invention also discloses a preparation method and an application of the polypeptide complex. In addition, the invention further discloses a pharmaceutical composition comprising the polypeptide complex.

The present invention belongs to the technical field of medicine, and specifically provides a glucagon-like peptide-1 analog dimer, the dimer is formed by two glucagon-like peptide-1 analog monomers, and the pancreatic Glucagon-like peptide-1 analogue monomer is formed by general formula HAX 1 GTFTSDVSSYLEGQAAKEFIX 2 WLVK X 3 RZ means, where Z is NH2, G, GNH2, ‑GCG, ‑GCA; X 1 For Leu, Pro, Phe, Tyr; X 2 For Ala, Cys; X 3 For Gly, Aib. and when X 2 When it is Ala, Z is ‑GCG, ‑GCA; when X 2 When it is Cys, Z is NH 2 ,G,GNH 2 . The glucagon-like peptide-1 analog dimer provided by the present invention has a long-acting hypoglycemic effect, can improve the compliance of clinical medication, and is highly homologous with endogenous GLP-1 (7-37), which can avoid security risk.

The invention provides a glucagon-like peptide-2 (GLP-2) analog, and a preparation method and an application thereof. The sequence of the GLP-2 analog is <1>HADX4SFSX8EMNTILDX16LAARDFIX24WLX27QTKITD<33>n1X1C n2X2 represented by SEQ ID NO:1, wherein X4 is glycine or cysteine; X8 is aspartic acid or cysteine; X16 is asparagine or cysteine; X24 is aspartic acid or cysteine; X27 is isoleucine or cysteine, only one of X4, X8, X16, X24 and X27 is cysteine, and cysteine is bonded with another cysteine through a disulfide bond; n1X1 represents n1 X1, and n1 is 1-30; and n2X2 represents n2 X2, and n2 is 0-30. The GLP-2 analog overcomes the short half life problem of GLP-2.

The invention discloses GLP-1 analogs, and a preparation method and an application thereof. The GLP-1 analogs have a following general formula A: <7>HAEX10TFTSDVSX18YLEX22QAX25KEFIX30WLX33KGRG<37>n1X1n2X2. With the GLP-1 analogs provided by the invention, GLP-1 blood half-life period can be effectively increased, such that a situation that GLP-1 cannot be clinically used due to short half-life period can be overcome. The GLP-1 analogs have application prospects in fields of medicines used for treating diabetes and obesity. The invention also discloses the preparation method and the application of the GLP-1 analogs.

The invention provides a long-acting glucagon-like peptide-1 analogue. The long-acting glucagon-like peptide-1 analogue is characterized in that the polypeptide has a structure shown as a general formula I: Z1-HX8EX10T FTSDV SSYLE X22QAAK EFIX30W LVKX35RG-Z2, wherein, any two residues of X8, X10, X22, X30, X35 are cysteine, Z2 is -H or -HN2; any one residue of X8, X10, X22, X30, X35 is cysteine, and Z2 is a -CG sequence. The glucagon-like peptide-1 analogue expressed by the general formula I always contains two cysteine residues to form an intramolecular disulfide bond, so that rapid degradation of the analogue in vivo is avoided, and the in-vivo half life is obviously prolonged.

The invention provides a GLP-1 (glucagon-like peptide-1) analogue modified with PEG (polyethylene glycol). The GLP-1analogue has an amino acid sequence shown in SEQ ID NO: 1-19, and the cysteine residue of the amino acid sequence is modified with a PEG group. The invention further provides an application of the analogue or analogue composition in preparation of drugs for treating diabetes, obesity and Alzheimer's disease. The polypeptide has better metabolism stability, has remarkably prolonged in-vivo half-life period, solves the problem that the half-life period of natural GLP-1 is short, can substantially improve the clinical application compliance and has higher application value.

The present invention provides an EXENDIN-4 analogue dimer and its preparation method and application. The dimer is composed of two identical or different EXENDIN-4 analogue monomers through cysteine ​​to form an inter-monomer disulfide bond, the preparation of the EXENDIN-4 analog dimer includes the synthesis of EXENDIN-4 analog monomers by Fmoc solid-phase peptide synthesis method, and then the monomers are formed into dimers; and the EXENDIN-4 is similar Application of the biodimer in the preparation of medicines for treating diabetes, treating and / or preventing obesity or obesity-related diseases. The half-life of the EXENDIN-4 analogue dimer formed by the monomer of the present invention can reach more than 14 to 96 hours in vivo, which is significantly longer than the half-life of EXENDIN-4 administered alone (half-life is only 2.4 hours), which is greatly convenient its clinical promotion and application.

The invention provides a monomer peptide of a glucagon-like peptide-1 analogue. The monomer peptide is represented by a general formula 1: Z<1>HAX<1>GTFTSDVSSYLE X<2>QAAKEFIAWLVKGRGCAX<3>, wherein Z<1> is H, acetyl or trifluoroacetyl; X<1> is Met, Leu, Pro, Phe, or Tyr; X<2> is Gly, Glu, or Aib (2-aminoisobutyric acid); and X<3> is NH<2> or H. The invention also provides a dimer formed by the monomer peptide, a preparation method of the dimer and applications of the dimer in preparing medicines. The dimer of the GLP-1 analogue monomer peptide provided by the invention has an obvious hypoglycemic effect, and the half-life in vivo can reach 12-72 hours or above, so that the problem of short half-life of natural GLP-1 is overcome and compliance of clinical application can be greatly improved.