Glucagon-like peptide-2 analogs
Analogs of glucagon-like peptide 2, a product of glucagon gene expression, have been identified as intestinal tissue growth factors. Their formulation as pharmaceutical, and therapeutic use in treating disorders of the small bowel, are described.
1. An intestinotrophic GLP-2 analog of SEQ ID NO: 2, wherein at least one amino acid at one or more positions selected from the group consisting of positions 1, 5, 7, 16-18, 25, and 33 is substituted with an amino acid other than a wild type, mammalian GLP-2 residue; wherein positions 2-4, 6, 8-15, 19-24, and 26-32 are unmodified, and wherein 4 to 8 residues are optionally deleted from the C-terminus of SEQ ID NO: 2.
2. The GLP-2 analog according to claim 1 , wherein said analog incorporates at least one amino acid substitution selected from the group consisting of:
a) incorporation of Pro, Asp, or desNH 2 Tyr at position 1;
b) incorporation of Thr or Ala at position 5;
c) incorporation of Ala at position 7;
d) incorporation of Ser at position 16;
e) incorporation of Arg at position 17;
f) incorporation of Arg at position 18;
g) incorporation of Phe or Tyr at position 25; and
h) incorporation of Glu at position 33.
3. The GLP-2 analog according to claim 1 selected from the group consisting of: [Pro 1 ]hGLP-2(1-33); [Asp 1 ]hGLP-2 (1-33); [desNH 2 Tyr 1 ]hGLP-2 (1-33); [Thr 5 ]hGLP-2 (1-33); [Ser 16 , Arg 17 , Arg 18 ]hGLP-2 (1-33); [Ala 5 , Ala 7 ]hGLP-2 (1-33); [Glu 33 ]hGLP-2 (1-33); [Phe 25 ]hGLP-2 (1-33); [Tyr 25 ]hGLP-2 (1-33).
4. A pharmaceutical composition comprising a therapeutically effective amount of a GLP-2 analog according to claim 1 and a pharmaceutically acceptable carrier.
5. A method for promoting growth of small bowel tissue in patient in need thereof, comprising the step of delivering to the patient the pharmaceutical composition of claim 4 .
6. A method for treating a gastrointestinal disease, wherein the method comprises administering to a patient having the gastrointestinal disease a therapeutically effective amount of a GLP-2 analog according to claim 1 , together with a pharmaceutically acceptable carrier to reduce a pathological effect or symptom of the gastrointestinal disease.
7. The method of claim 6 , wherein the gastrointestinal disease is selected from the group consisting of ulcers, digestion disorders, malabsorption syndromes, short-gut syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis (Crohn's disease), small intestinal damage due to toxic or other chemotherapeutic agents, and short bowel syndrome.
8. A method for promoting growth of small bowel tissue in a patient in need thereof, comprising the step of delivering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a GLP-2 analog according to claim 3 .
9. A method for treating a gastrointestinal disease, wherein the method comprises administering to a patient having the gastrointestinal disease a therapeutically effective amount of a GLP-2 analog according to claim 3 together with a pharmaceutically acceptable carrier to reduce a pathological effect or symptom of the gastrointestinal disease.
10. The method of claim 9 , wherein the gastrointestinal disease is selected from the group consisting of ulcers, digestion disorders, malabsorption syndromes, short-gut syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis (Crohn's disease), small intestinal damage due to toxic or other chemotherapeutic agents, and short bowel syndrome.
11. A method of identifying intestinotrophic analogs of GLP-2, comprising the steps of:
a. obtaining a GLP-2 analog according to claim 1 ;
b. treating a mammal with said analog using a regimen capable of eliciting an intestinotrophic effect when utilized for rat GLP-2; and
c. determining the effect of said analog on small bowel weight relative to a mock treated control mammal, whereby said intestinotrophic analog of GLP-2 is identified as an analog which elicits an increase in said weight.
12. A method for promoting growth of small bowel tissue in a patient in need thereof, comprising the step of delivering to the patient a pharmaceutical composition comprising the GLP-2 analog of claim 1 .
13. The peptide [desNH 2 Tyr 1 ]hGLP-2(1-33).