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Long lasting glucagon-like peptide 2 (GLP-2) for the treatment of gastrointestinal diseases and disorders

  • US 7,737,251 B2
  • Filed: 12/23/2005
  • Issued: 06/15/2010
  • Est. Priority Date: 02/16/2001
  • Status: Expired due to Fees
First Claim
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1. A gastrointestinal tissue growth promoter derivative comprising:

  • a GLP-2 peptide having gastrointestinal tissue growth promoting activity; and

    a single maleimide or a maleimido-containing group, wherein the maleimide or maleimido-containing group is coupled, optionally via a linker, to the GLP-2 peptide at a His or Lys residue,wherein the GLP-2 peptide is of the sequence;

    R1-(Y1)m-X1-X2-X3-X4-X5-Phe6-Ser7-Asp8-(P1)-X14-Asp15-X16-X17-Ala18-X19-X20-X21-Phe22-(P2)-Trp25-Leu26-X27-X28-Thr29-Lys30-P3-(Y2)n-R2(SEQ ID NOs;

    2 and 29-252) whereinX1 is His or Tyr;

    X2 is Gly, D-Ala, Pro, Ile, Nor-Val, α

    -aminobutyric acid, or an Ala-replacement amino acid conferring on said analog resistance to DPP-IV enzyme;

    X3 is Asp, Glu, Pro, HPro;

    or X2-X3 are X

    (CH(OH)CH2)X3;

    X

    (CH2NH2)X3 or X

    (CHCH)X3 wherein X2 and X3 are as defined above;

    X4is Gly or Ala;

    X5 is Ser or Ala;

    P1 is Glu-X10-Asn-Thr-Ile (SEQ ID NO;

         253), Gly-X10-Asn-Thr-Val (SEQ ID NO;

         254) or Tyr-Ser-Lys-Tyr (SEQ ID NO;

         255);

    X10is Met, Leu, Ile or an oxidatively stable Met-replacement amino acid;

    X14 is Leu or Lys;

    X16 is Asn, Lys or Ala;

    X17 is Leu or Lys;

    X19 is Ala or Thr;

    X20 is Arg, Lys, His or Ala;

    X21 is Asp or Lys;

    X27 is Ile or Leu;

    X28 is Gin or His;

    P2 is IIe-Asn, lIe-Ala or Val-Gin;

    P3 is a covalent bond, or is lIe, Ile-Thr, Ile-Thr-Asp or Ile-Thr-Asn;

    R1 is NH2 or a N-terminal blocking group;

    R2 is COOH, CONH2 or a C-terminal blocking group;

    Y1 is one or two of Arg, Lys, and His;

    Y2 is one or two of Arg, Lys, and His; and

    m and n are independently 0 or 1.

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