Bioconjugates of synthetic apelin polypeptides

A bioconjugate or a multimer thereof, comprising:

• a. a peptide or polypeptide having the following formula I′ (SEQ ID NO:
• 1):
• wherein:
• X1 is the N-terminus of the polypeptide and is either absent or is selected from pE, R, lsn, Q, A, K, and 5-amino-valeric acid;
• X2 is R, A, r, N-Me-R, K, H, hF, hK, F, E or Orn;
• X3 is P, A, a, p, 4-PhP, K, D, pipecolic acid, or cysteine wherein the side chain of cysteine forms a disulfide bond with the side chain of the cysteine at the X7 position;
• X4 is R, A, r, N-Me-R, F, E or cysteine wherein the side chain of cysteine forms a disulfide bond with the side chain of the cysteine at the X7 position;
• X5 is L, Cha, A, D-L, N-Me-L, K, D, 4-PhF or F;
• X6 and X12 are independently a natural or unnatural amino acid selected from C, c, hC, D-hC, K, D, Orn, Dab or E wherein the side chain of X6 and X12 are linked together via a covalent bond forming either a monosulfide (—S—), a disulfide (—S—S—) or an amide bond (—NHC(O)— or —C(O)—NH—);
• or alternatively X6 is K, X13 is absent and X12 is F or f wherein the C-terminus of X12 form an amide bond with the amino side chain of X6;
• X7 is H, h, A, N-Me-A, a, Aib, K, Nal, F, P, Dap, N, E or cysteine wherein the side chain of the cysteine forms a disulfide bond with the side chain of the cysteine at position X3 or with the side chain of the cysteine at position X4;
• X8 is K, k, F, f, A, hF, N-Me-R, E or 4-amino-lsn;
• X9 is G, N-Me-G, A, D, L, R or Aib;
• X10 is P, A, p, 4-PhP or pipecolic acid,
• X11 is M, D-Nle, Nle, N-Me-Nle, M(O), A, F, Y, L, K, 3-PyA or Cha;
• and
• X13 is the C-terminus and is absent or is selected from F, f, N-Me-F, Nal, D-Nal, 3-Br-F, (S)-β-3-F, I, A, a, K, Dap, H and E;
• wherein:
• Nle is L-norleucine;
• D-hC is D-homocysteine
• hC is L-homocysteine;
• hF is L-homophenylalanine;
• hK is L-lysine;
• Nal is L-naphathaline;
• Orn is ornithine;
• Aib is □-aminoisobutyric acid;
• Dab is (S)-diaminobutyric acid;
• Dap is (S)-2,3-diaminopropionic acid;
• M(O) is methionine sulfone;
• Cha is (S)-β-cyclohexylalanine;
• 4-amino-lsn is 4-aminopiperidine-4-carboxylic acid;
• lsn is isonipecotinoyl;
• pE is L-pyroglutamic acid;
• 3-PyA is 3-(3-pyridyl)-L-alanine;
• 4-PhF is 4-Phenyl-L-phenylalanine;
• wherein the N-terminus and the C-terminus optionally form a ring together with 1, 2, 3 or 4 glycine amino acids;
• and
• or an amide, an ester or a salt of the polypeptide;
• or a polypeptide substantially equivalent thereto;
• and
• b. a half-life extending moiety;
• and wherein said peptide or polypeptide and half-life extending moiety are covalently linked or fused optionally via a linker.