Glucagon-receptor selective polypeptides and methods of use thereof

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.