Modified exendins and exendin agonists
First Claim
1. A compound comprising exendin-4, or agonist analog of exendin-4, linked to a polyamino acid through the C-terminal amino acid of the exendin-4 or agonist analog of exendin-4, wherein the agonist analog of exendin-4 comprises one or more naturally occurring amino acids deleted or replaced with another amino acid or amino acids and said polyamino acid is selected from the group consisting of poly(L-lysine), poly-glutamic acid, and poly-aspartic acid.
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Accused Products
Abstract
Novel modified exendins and exendin agonists having an exendin or exendin agonist linked to one or more polyethylene glycol polymers, for example, and related formulations and dosages and methods of administration thereof are provided. These modified exendins and exendin agonists, compositions and methods are useful in treating diabetes and conditions that would be benefited by lowering plasma glucose or delaying and/or slowing gastric emptying or inhibiting food intake.
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Citations
12 Claims
- 1. A compound comprising exendin-4, or agonist analog of exendin-4, linked to a polyamino acid through the C-terminal amino acid of the exendin-4 or agonist analog of exendin-4, wherein the agonist analog of exendin-4 comprises one or more naturally occurring amino acids deleted or replaced with another amino acid or amino acids and said polyamino acid is selected from the group consisting of poly(L-lysine), poly-glutamic acid, and poly-aspartic acid.
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4. A compound comprising an agonist analog of exendin-4, wherein said agonist analog of exendin-4 is linked to a polyamino acid through the C-terminal amino acid of said agonist analog of exendin-4;
- and the polyamino acid is selected from the group consisting of poly(L-lysine), polyglutamic acid, and poly-aspartic acid; and
comprises the amino acid sequence of SEQ ID NO;
200, said sequence comprising;Xaa1 Xaa2 Xaa3 Gly Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 Xaa12 Xaa13 Xaa14 Xaa15 Xaa16 Xaa17 Ala Xaa19 Xaa20 Xaa21 Xaa22 Xaa23 Xaa24 Xaa25 Xaa26 Xaa27 Xaa28-Z1; wherein; Xaa1 is His, Arg, Tyr, Ala, Norval, Val or Norleu; Xaa2 is Ser, Gly, Ala or Thr; Xaa3 is Asp or Glu; Xaa5 is Ala or Thr; Xaa6 is Phe, Tyr or naphthylalanine; Xaa7 is Thr or Ser; Xaa8 is Ala, Ser or Thr; Xaa9 is Asp or Glu; Xaa10 is Ala, Leu, Ile, Val, pentylglycine or Met; Xaa11 is Ala or Ser; Xaa12 is Ala or Lys; Xaa13 is Ala or Gln; Xaa14 is Ala, Leu, Ile, pentylglycine, Val or Met; Xaa15 is Ala or Glu; Xaa16 is Ala or Glu; Xaa17 , is Ala or Glu; Xaa19 is Ala or Val; Xaa20 is Ala or Arg; Xaa21 is Ala or Leu; Xaa22 is Phe, Tyr or naphthylalanine; Xaa23 is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaa24 is Ala, Glu or Asp; Xaa25 is Ala, Trp, Phe, Tyr or naphthylalanine; Xaa26 is Ala or Leu; Xaa27 is Ala or Lys; Xaa28 is Ala or Asn; Z1 is —
OH,—
NH2,Gly Gly-Z2, Gly Gly Xaa31-Z2, Gly Gly Xaa31 Ser-Z2 [SEQ ID NO;
241],Gly Gly Xaa31 Ser Ser-Z2 [SEQ ID NO;
242],Gly Gly Xaa31 Ser Ser Gly-Z2 [SEQ ID NO;
243],Gly Gly Xaa31 Ser Ser Gly Ala-Z2 [SEQ ID NO;
253],Gly Gly Xaa31 Ser Ser Gly Ala Xaa36-Z2 [SEQ ID NO;
254],Gly Gly Xaa31 Ser Ser Gly Ala Xaa36 Xaa37-Z2 [SEQ ID NO;
245],Gly Gly Xaa31 Ser Ser Gly Ala Xaa36 Xaa37 Xaa38-Z2 [SEQ ID NO;
256], orGly Gly Xaa31 Ser Ser Gly Ala Xaa36 Xaa37 Xaa38 Xaa39-Z2 [SEQ ID NO;
251] consensus disclosed as [SEQ ID NO;
203] wherein;Xaa31, Xaa36, Xaa37 and Xaa38 are independently; Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; and
;Z2 is —
OH or —
NH2;provided that no more than three of Xaa3, Xaa4, Xaa5, Xaa6, Xaa8, Xaa9, Xaa10, Xaa11, Xaa12, Xaa13, Xaa14, Xaa15, Xaa16, Xaa17, Xaa19, Xaa20, Xaa21, Xaa24, Xaa25, Xaa26, Xaa27 and Xaa28 are Ala; and
provided also that, if Xaa1 is His, Arg or Tyr, then at least one of Xaa3, Xaa4 and Xaa9 is Ala; and
Xaa39 is Ser or Tyr. - View Dependent Claims (5, 6, 10, 11, 12)
- and the polyamino acid is selected from the group consisting of poly(L-lysine), polyglutamic acid, and poly-aspartic acid; and
Specification