Long acting peptide tyrosine tyrosine (pyy) analogs and methods of use

A method of treating obesity in a human subject, providing weight loss to the human subject, or suppressing appetite in the human subject comprising administering to the subject in need thereof:

• (i) an isolated polypeptide, comprising the amino acid sequence of SEQ ID NO:
• 90:
• X0PX2PX4X5PX7X8X9X10SPX13X14X15X16RX18X19X20DX22X23HX25X26X27WLTRX32RX34-(OH/NH2) (SEQ ID NO:
• 90), or a pharmaceutically acceptable salt thereof, wherein:
• X0 is absent or K;
• X2 is K;
• X4 is E or K;
• X5 is A or K;
• X7 is G or K
• X8 is E, K, or k;
• X9 is D or K;
• X10 is A or K;
• X13 is E or K;
• X14 is E or K;
• X15 is L or W;
• X16 is D, E, K, N, Q, S, T, α-methylserine, or homoserine;
• X18 is K or Y;
• X19 is K or Y;
• X20 is A, D, E, K, k, or Dap,
• X22 is A, D, K, or L;
• X23 is K or R;
• X25 is K or Y;
• X26 is E, K, or L;
• X27 is K or N;
• X32 is K or Q;
• X34 is F, y, 3-pyridinylalanine, 4-pyridinylalanine, 4-carboxyphenylalanine, 4-fluorophenylalanine, 4-methylphenylalanine, N-methylphenylalanine, homophenylalanine, β-homotyrosine, homotyrosine, or N-methyltyrosine;
• wherein when X0, X2, X4, X5, X7, X8, X13, X20, X23, X25, X27, or X32 are K, the lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer, and
• wherein when X8 or X20 are k, the D-lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer,
• provided that the polypeptide comprises at least one residue covalently bound to lipophilic substituent, optionally via a spacer;
• and
• wherein the polypeptide optionally further comprises a lactam bridge formed via an amide bond between the side chains of a lysine and an aspartic acid or between the side chains of a lysine and a glutamic acid, wherein the residues that form the lactam bridge are located at positions X9 and X13 or at positions X16 and X20 or at positions X22 and X26;
• and
• (ii) a GLP-1 receptor agonist.