34 results about "Glucagon-like peptide-2" patented technology

GLP-2 analogues are disclosed which comprise one of more substitutions as compared to [hGly2]GLP-2 and which improved biological activity in vivo and / or improved chemical stability, e.g., as assessed in in vitro stability assays. More particularly, preferred GLP-2 analogues disclosed herein comprise substitutions at one or more of positions 8, 16, 24 and / or 28 of the wild-type GLP-2 sequence, optionally in combination with further substitutions at position 2 (as mentioned in the introduction) and one or more of positions 3, 5, 7, 10 and 11, and / or a deletion of one or more of amino acids 31 to 33 and / or the addition of a N-terminal or C-terminal stabilizing peptide sequence. The analogues are particularly useful for the prophylaxis or treatment of stomach and bowel-related disorders and for ameliorating side effects of chemotherapy. Also disclosed are methods and kits for selecting a patient from populations suited for treatment with GLP-2 analogues.

This invention relates to glucagon-like peptide 2 (GLP-2) derivatives. In particular this invention relates to GLP-2 peptide derivatives having an extended in vivo half-life, for the treatment or prevention of gastrointestinal disorders or diseases such as inflammatory bowel disease and other gastrointestinal functions, from any segment of the gastrointestinal tract, from the oesophagus to the anus.

GLP-2 analogues are disclosed which comprise one of more substitutions as compared to h[Gly2]GLP-2 and which may have the property of an increased small intestine / colon and stomach / colon selectivity. More particularly, preferred GLP-2 analogues disclosed herein comprise substitutions at one or more of positions 11, 16, 20, 24 and / or 28 of the wild-type GLP-2 sequence, optionally in combination with further substitutions at position 2 and one or more of positions 3, 5, 7, and 10, and / or a deletion of one or more of amino acids 31 to 33 and / or the addition of a N-terminal or C-terminal stabilizing peptide sequence. The analogues are particularly useful for the prophylaxis or treatment of stomach and bowel-related disorders and for ameliorating side effects of chemotherapy.

The present invention relates to a glucagon-like peptide-2 (GLP-2) conjugate comprising native GLP-2 or its derivative and an immunoglobulin Fc fragment being covalently linked via a non-peptidyl polymer, wherein the native GLP-2 or its derivative has a thiol group introduced at its C-terminal end, and one end of the non-peptidyl polymer is linked to an amino acid residue of the GLP-2 other than the N-terminal amino group thereof; a method for preparing the GLP-2 conjugate; a pharmaceutical composition comprising the same; and a method for treating or preventing intestinal disease, intestinal injury, or gastrosia by using the same. Since the GLP-2 conjugate of the present invention has a remarkably increased binding affinity to a GLP-2 receptor, it shows a prolonged in vivo half-life and an improved in vivo durability and stability.

GLP-2 analogues are disclosed which comprise one of more substitutions as compared to [hGly2]GLP-2 and which improved biological activity in vivo and / or improved chemical stability, e.g. as assessed in in vitro stability assays. More particularly, preferred GLP-2 analogues disclosed herein comprise substitutions at one or more of positions 8, 16, 24 and / or 28 of the wild-type GLP-2 sequence, optionally in combination with further substitutions at position 2 (as mentioned in the introduction) and one or more of positions 3, 5, 7, 10 and 11, and / or a deletion of one or more of amino acids 31 to 33 and / or the addition of a N-terminal or C-terminal stabilizing peptide sequence. The analogues are particularly useful for the prophylaxis or treatment of stomach and bowel-related disorders and for ameliorating side effects of chemotherapy.

The present invention relates to novel human glucagon-like peptide-2 (GLP-2) peptides and human glucagon-like peptide-2 derivatives which have a protracted profile of action as well as polynucleotide constructs encoding such peptides, vectors and host cells comprising and expressing the polynucleotide, pharmaceutical compositions, uses and methods of treatment.

The invention belongs to the field of medical biotechnology, and relates to two series major vault protein of glucagon-like peptide-2 (GLP-2) of people and a preparation method of the two series major vault protein. A second place of an amino acid fragment of the glucagon-like peptide-2 of people is mutated, two segments are connected in series through connecting peptide, a dimmer structure of the GLP-2 is simulated, encoding gene of the two series major vault protein of the GLP-2 is obtained by a synthetic method, the encoding gene is cloned to a pET22b(+) pronucleus so as to express a vector, Escherichia coli BL21 is transformed, the encoding gene is expressed in the Escherichia coli efficiently, the purified reconstructed purpose protein is obtained through salt fractionation of ammonium sulfate in fractional and chromatography of anion exchange columns. The reconstructed purpose protein can stimulate a Caco-2 cell, multiplication of the Caco-2 cell can be promoted notably, the two series major vault protein of GLP-2 of people has natural biological activities, and therefore a foundation is established for further study and extensive use of the GLP-2 of people.

GLP-2 analogues are disclosed which comprise one of more substitutions as compared to h[Gly2]GLP-2 and which may have the property of an increased small intestine / colon and stomach / colon selectivity. More particularly, preferred GLP-2 analogues disclosed herein comprise substitutions at one or more of positions (11, 16, 20, 24) and / or (28) of the wild-type GLP-2 sequence, optionally in combination with further substitutions at position (2) and one or more of positions (3, 5, 7), and (10), and / or a deletion of one or more of amino acids (31) to (33) and / or the addition of a N-terminal or C-terminal stabilizing peptide sequence. The analogues are particularly useful for the prophylaxis or treatment of stomach and bowel-related disorders and for ameliorating side effects of chemotherapy.

The present invention relates to novel derivatives of human glucagon-like peptide-2 (GLP-2) peptides, which have a protracted profile of action, as well as pharmaceutical compositions, uses and methods of treatment.

The present invention relates to novel glucagon peptides, to the use of said glucagon peptides in therapy, to methods of treatment comprising administration of said glucagon peptides to patients in need thereof, and to the use of said glucagon peptides in the manufacture of medicaments. The glucagon peptides of the present invention are of particular interest in relation to the treatment of hyperglycemia, diabetes and obesity, as well as a variety of diseases or conditions associated with hyperglycemia, diabetes and obesity.

GLP-2 analogues are disclosed which comprise one of more substitutions as compared to h[Gly2]GLP-2 and which may have the property of an altered GLP-1 activity, and their medical use. The analogues are particularly useful for the prophylaxis, treatment or ameliorating of the gastro-intestinal associated side effects of diabetes.

The present invention provides pharmaceutical agents comprising a dipeptidyl peptidase IV (DPPIV) inhibitor and a biguanide agent in combination, which enhance the effects of active circulating glucagon-like peptide-1 (GLP-1) and / or active circulating glucagon-like peptide-2 (GLP-2).

The invention provides a glucagon-like peptide-2 poly(ethylene glycol) conjugate, which is acquired by modifying glucagon-like peptide-2 with poly(ethylene glycol), wherein each glucagon-like peptide-2 covalently bonds with one poly(ethylene glycol) molecule. The invention also provides a preparation method and application of the glucagon-like peptide-2 poly(ethylene glycol) conjugate. According to the invention, a glucagon-like peptide-2 poly(ethylene glycol) conjugate with good efficacy and long half-life period is acquired by optimizing PEGylation reaction conditions; and if used clinically, the glucagon-like peptide-2 poly(ethylene glycol) conjugate is administered only 1-2 times a week, thus greatly reducing the pain of patients. Meanwhile, the recombinant production method of GLP-2 (glucagon-like peptide-2) provided by the invention is simple and safe, greatly lowers the cost in the preparation of the glucagon-like peptide-2 poly(ethylene glycol) conjugate, and has a good application prospect.

Provided are a glucagon-like peptide-2 (GLP-2) conjugate containing native GLP-2 or its derivative and an immunoglobulin Fc fragment being covalently linked via a non-peptidyl polymer, wherein the native GLP-2 or its derivative has a thiol group introduced at its C-terminal end, and one end of the non-peptidyl polymer is linked to an amino acid residue of the GLP-2 other than the N-terminal amino group thereof; a method for preparing the GLP-2 conjugate; a pharmaceutical composition comprising the same; and a method for treating or preventing intestinal disease, intestinal injury, or gastrosis by using the same. Since the GLP-2 conjugate of the present invention has a remarkably increased binding affinity to a GLP-2 receptor, it shows a prolonged in vivo half-life and an improved in vivo durability and stability.

Glucagon-like peptide-2, a product of glucagon gene expression, and analogs of glucagon-like peptide-2, have been identified as gastrointestinal tissue growth factors. Their effects on the growth of small bowel and pancreatic islets are described. Their formulation as a pharmaceutical, and their therapeutic use in treating disorders of the bowel, are described.

Glucagon-like peptide 2, a product of glucagon gene expression, and analogs of glucagon-like peptide 2, have been identified as gastrointestinal tissue growth factors. Their effects on the growth of small bowel and pancreatic islets are described. Their formulation as a pharmaceutical, and their therapeutic use in treating disorders of the bowel, are described.

The present invention relates a method of preparing a Glucagon-like peptide 2 (GLP-2) analog by gene recombination. The present invention provides an expression vector, which includes: (a) a nucleic acid sequence encoding tag protein; (b) a nucleic acid sequence encoding Smt3 protein (SEQ ID NO: 1); and (c) a nucleic acid sequence encoding linker peptide (SEQ ID NO: 2) and GLP-2 analog. The fusion protein expressed by the expression vector can be cleaved by thrombin, wherein the cleaving position is at the linker peptide, and then the GLP-2 analog is produced.

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.

GLP-2 analogues are disclosed which comprise one of more substitutions as compared to [hGly2]GLP-2 and which improved biological activity in vivo and / or improved chemical stability, e.g., as assessed in in vitro stability assays. More particularly, preferred GLP-2 analogues disclosed herein comprise substitutions at one or more of positions 8, 16, 24 and / or 28 of the wild-type GLP-2 sequence, optionally in combination with further substitutions at position 2 (as mentioned in the introduction) and one or more of positions 3, 5, 7, 10 and 11, and / or a deletion of one or more of amino acids 31 to 33 and / or the addition of a N-terminal or C-terminal stabilizing peptide sequence. The analogues are particularly useful for the prophylaxis or treatment of stomach and bowel-related disorders and for ameliorating side effects of chemotherapy. Also disclosed are methods and kits for selecting a patient from populations suited for treatment with GLP-2 analogues.

The invention discloses a construction method and application of recombinant lactobacillus acidophilus for expressing glucagon-like peptide-2. The construction method comprises the following steps: designing a primer containing specific restriction enzyme digestion site according to gene sequence and expression vector plasmid characteristic of disclosed glucagon-like peptide-2; by using small intestinal mucosa as a material, carrying out RT-PCR (reverse transcription-polymerase chain reaction) to obtain fragment containing glucagon-like peptide-2 gene; connecting the fragment with lactobacillus expression vector plasmid Pmg36e to obtain recombinant plasmid Pmg36e-glp2; transferring the recombinant plasmid in actobacillus acidophilus through an electrotransformation method to obtain recombinant lactobacillus acidophilus for expressing glucagon-like peptide-2; expressing under the induction of nisin; and analyzing and proving that the gene is correctly expressed through SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) and Western blot. The recombinant lactobacillus acidophilus is used for preventing and treating diarrhea, improving the intestinal health of pig and improving the growth performance.

GLP-2 peptides and analogs thereof are produced in high yield and with desired, authentic termini by isolation from a GLP-2 peptide multimer in which at least two units of GLP-2 peptide are coupled through a linker that presents an N-terminal acid cleavage site and a C-terminal enzyme cleavage site. In a specific embodiment, [Gly2]hGLP-2 is produced from a multimeric precursor comprising 2-30 units thereof.

The invention relates to a new GLP-2 analog and a preparation method thereof. Compared with natural GLP-2, the GLP-2 analog has the advantages of improved chemical stability, and reservation of the pharmacological activities of the natural GLP-2. The GLP-2 analog has a chemical structure represented by a formula shown in the specification.

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-2 peptides and analogs thereof are produced in high yield and with desired, authentic termini by isolation from a GLP-2 peptide multimer in which at least two units of GLP-2 peptide are coupled through a linker that presents an N-terminal acid cleavage site and a C-terminal enzyme cleavage site. In a specific embodiment, [Gly2]hGLP-2 is produced from a multimeric precursor comprising 2-30 units thereof.

Glucagon peptides with increased GIP activity are provided, optionally with GLP-I and / or glucagon activity. In some embodiments, C-terminally extended glucagon peptides comprising an amino acid sequence substantially similar to native glucagon are provided herein.

GLP-2 analogues are disclosed which comprise one of more substitutions as compared to [hGly2]GLP-2 and which improved biological activity in vivo and / or improved chemical stability, e.g., as assessed in in vitro stability assays. More particularly, preferred GLP-2 analogues disclosed herein comprise substitutions at one or more of positions 8, 16, 24 and / or 28 of the wild-type GLP-2 sequence, optionally in combination with further substitutions at position 2 (as mentioned in the introduction) and one or more of positions 3, 5, 7, 10 and 11, and / or a deletion of one or more of amino acids 31 to 33 and / or the addition of a N-terminal or C-terminal stabilizing peptide sequence. The analogues are particularly useful for the prophylaxis or treatment of stomach and bowel-related disorders and for ameliorating side effects of chemotherapy. Also disclosed are methods and kits for selecting a patient from populations suited for treatment with GLP-2 analogues.

The invention discloses a construction method and application of recombinant lactobacillus acidophilus for expressing glucagon-like peptide-2. The construction method comprises the following steps: designing a primer containing specific restriction enzyme digestion site according to gene sequence and expression vector plasmid characteristic of disclosed glucagon-like peptide-2; by using small intestinal mucosa as a material, carrying out RT-PCR (reverse transcription-polymerase chain reaction) to obtain fragment containing glucagon-like peptide-2 gene; connecting the fragment with lactobacillus expression vector plasmid Pmg36e to obtain recombinant plasmid Pmg36e-glp2; transferring the recombinant plasmid in actobacillus acidophilus through an electrotransformation method to obtain recombinant lactobacillus acidophilus for expressing glucagon-like peptide-2; expressing under the induction of nisin; and analyzing and proving that the gene is correctly expressed through SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) and Western blot. The recombinant lactobacillus acidophilus is used for preventing and treating diarrhea, improving the intestinal health of pig and improving the growth performance.