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Glucagon-receptor selective polypeptides and methods of use thereof

  • US 10,501,517 B2
  • Filed: 05/15/2017
  • Issued: 12/10/2019
  • Est. Priority Date: 05/16/2016
  • Status: Active Grant
First Claim
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1. An isolated polypeptide comprising:

  • (i) the amino acid sequence;

    X1X2X3GTFTSDX10X11X12X13LX15X16X17X18AQEFX23X24X25LEDE-Z-tail (SEQ ID NO;

         1), wherein;

    X1 is Y or W;

    X2 is S, G or T;

    X3 is Q or H;

    X10 is Y or H;

    X11 is S or T;

    X12 is K or R;

    X13 is Y, L or W;

    X15 is D or E;

    X16 is S, 2-Aminoisobutyric acid (Aib), A, E, L, Q, K, or I;

    X17 is K, E, S, T, or A;

    X18 is A, R, S, E, L, T or Y;

    X23 is T or V;

    X24 is K, I, L, or Aib;

    X25 is H or W; and

    Z-tail is absent;

    or is selected from the group consisting of EEPSSGAPPPS-OH (SEQ ID NO;

         4);

    EPSSGAPPPS-OH (SEQ ID NO;

         5);

    GAPPPS-OH (SEQ ID NO;

         6);

    GGPSSGAPPPS-OH (SEQ ID NO;

         7);

    GPSSGAPPPS-OH (SEQ ID NO;

         8);

    KRNKNPPPS-OH (SEQ ID NO;

         9);

    KRNKNPPS-OH (SEQ ID NO;

         10);

    KRNKPPIA-OH (SEQ ID NO;

         11);

    KRNKPPPA-OH (SEQ ID NO;

         150);

    KRNKPPPS-OH (SEQ ID NO;

         12);

    KSSGKPPPS-OH (SEQ ID NO;

         13);

    PESGAPPPS-OH (SEQ ID NO;

         14);

    PKSGAPPPS-OH (SEQ ID NO;

         15);

    PKSKAPPPS-NH2 (SEQ ID NO;

         16);

    PKSKAPPPS-OH (SEQ ID NO;

         17);

    PKSKEPPPS-NH2 (SEQ ID NO;

         18);

    PKSKEPPPS-OH (SEQ ID NO;

         19);

    PKSKQPPPS-OH (SEQ ID NO;

         20);

    PKSKSPPPS-NH2 (SEQ ID NO;

         21);

    PKSKSPPPS-OH (SEQ ID NO;

         22);

    PRNKNNPPS-OH (SEQ ID NO;

         23);

    PSKGAPPPS-OH (SEQ ID NO;

         24);

    PSSGAPPPSE-OH (SEQ ID NO;

         25);

    PSSGAPPPS-NH2 (SEQ ID NO;

         26);

    PSSGAPPPS-OH (SEQ ID NO;

         27);

    PSSGAPPPSS-OH (SEQ ID NO;

         28);

    PSSGEPPPS-OH (SEQ ID NO;

         29);

    PSSGKKPPS-OH (SEQ ID NO;

         30);

    PSSGKPPPS-NH2 (SEQ ID NO;

         31);

    PSSGKPPPS-OH (SEQ ID NO;

         32);

    PSSGSPPPS-OH (SEQ ID NO;

         33);

    PSSKAPPPS-OH (SEQ ID NO;

         34);

    PSSKEPPPS-OH (SEQ ID NO;

         35);

    PSSKGAPPPS-OH (SEQ ID NO;

         36);

    PSSKQPPPS-OH (SEQ ID NO;

         37);

    PSSKSPPPS-OH (SEQ ID NO;

         38);

    SGAPPPS-OH (SEQ ID NO;

         39); and

    SSGAPPPS-OH (SEQ ID NO;

         40);

    or(ii) the amino acid sequence;

    YSQGTFTSDYSKYLDSX17RAQX21FVX24WLX27X28T-OH (SEQ ID NO;

         137),wherein;

    X17 is K*, where K* is in a lactam bridge with E* at X21;

    X21 is E*, where E* is in a lactam bridge with K* at X17;

    X24 is K or K**, where K** is in a lactam bridge with E** at X28;

    X27 is Q or D; and

    X28 is E or E**, where E** is in a lactam bridge with K** at X24;

    or(iii) the amino acid sequence;

    X1SX3GTFTSDX10SKYLDX16X17X18AQX21FVX24WLEDEPX31SX33X34PPPS-OH (SEQ ID NO;

         151),wherein;

    X1=Y or W;

    X3=H or Q;

    X10=Y, K or K***;

    X16=A, S, Aib, K or K***;

    X17=A, K, Aib or K***;

    X18=Y, S or R;

    X21=E, K or K***;

    X24=I, Aib, K or K***;

    X31=S, K or K***;

    X33=G, K or K***; and

    X34=A or S;

    wherein K*** is lysine, and the ε

    -amino group of the lysine sidechain is covalently joined to a lipophilic substituent, optionally via a spacer.

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