Conjugates of lipophilic moieties and fragments of vasoactive intestinal peptide (VIP)

Claim 1

A conjugate of a peptide coupled to a lipophilic moiety, wherein the peptide has at least 3 and at most 12 amino acid residues, said conjugate being selected from the formulae: (i) R 1 -X 1 -X 1 ′-X 1 ″-X 2 -NH—R 2 (SEQ ID NO:2); (ii) R 1 -X 3 -Ser-X 4 -Leu-Asn-NH—R 2 (SEQ ID NO:3); wherein R 1 is H or a lipophilic moiety; R 2 is H, a lipophilic moiety, a lipophilic moiety substituted by X 3 -Ser-X 4 -Leu-Asn-NHR 1 (SEQ ID NO:79) or a spacer consisting of 1-3 residues of a non-charged amino acid coupled to X 1 -X 1 ′-X 1 ″-X 2 -NHR 1 (SEQ ID NO:80), with the proviso that at least one of R 1 and R 2 is a lipophilic moiety; X 1 is a covalent bond, Ala, Val, Ala-Val, Val-Ala, L-Lys, D-Lys, Ala-Lys, Val-Lys, Ala-Val-Lys; Val-Ala-Lys or Orn; X 1 ′ is L-Lys, D-Lys or Orn; X 1 ″ is L-Tyr, D-Tyr, Phe, Trp or the residue of p-amino phenylalanine; X 4 is Ile or Tyr; X 5 is a residue of a hydrophobic aliphatic amino acid; X 2 is X 5 , X 5 -Asn, X 5 -Ser, X 5 -Ile, X 5 -Tyr, X 5 -Leu, X 5 -Nle, X 5 -D-Ala, X 5 -Asn-Ser, X 5 -Asn Ser-Ile (residues 1-4 of SEQ ID NO:75), X 5 -Asn-Ser-Tyr (residues 1-4 of SEQ ID NO:76), X 5 -Asn-Ser-Ile-Leu (residues 1-5 of SEQ ID NO:75), X 5 -Asn-Ser-Tyr-Leu (residues 1-5 of SEQ ID NO:76), X 5 -Asn-Ser-Tyr-Leu (residues 1-5 of SEQ ID NO:76), X 5 -Asn-Ser-Ile-Leu-Asn (SEQ ID NO:75) or X 5 -Asn-Ser-Tyr-Leu-Asn (SEQ ID NO:76); X 3 is a covalent bond, Asn, X 5 , X 5 -Asn, Tyr-X 5 , Tyr-X 5 -Asn, Lys-X 5 , Lys-X 5 -Asn, Lys-Tyr-X 5 , Lys-Tyr-X 5 -Asn (residues 4-7 of SEQ ID NO:77), Lys-Lys-Tyr-X 5 (residues 3-6 of SEQ ID NO:77), Lys-Lys-Tyr-X 5 -Asn (residues 3-7 of SEQ ID NO:77), Val-Lys-Lys-Tyr-X 5 (residues 2-6 of SEQ ID NO:78), Val-Ala-Lys-Lys-Tyr-X 5 -Asn (SEQ ID NO:77), or Ala-Val-Lys-Lys-Tyr-X 5 -Asn (SEQ ID NO:78); X 6 is a covalent bond or Asn, Ser, Ile, Tyr, Leu, Asn-Ser, Asn-Ser-Ile, Asn-Ser-Tyr, Asn-Ser-Ile-Leu (residues 2-5 of SEQ ID NO:75), Asn-Ser-Tyr-Leu (residues 2-5 of SEQ ID NO:76), Asn-Ser-Ile-Leu-Asn (residues 2-6 of SEQ ID NO:75) or Asn-Ser-Tyr-Leu-Asn (residues 2-6 of SEQ ID NO:76); X 7 is a covalent bond or Asn; X 8 is a covalent bond, X 5 , Tyr, Lys, Tyr-X 5 , Lys-X 5 , Lys-Tyr-X 5 , Lys-Lys-Tyr-X 5 (residues 3-6 of SEQ ID NO:77), Val-Lys-Lys-Tyr-X 5 (residues 2-6 of SEQ ID NO:78), Ala-Lys-Lys-Tyr-X 5 (residues 2-6 of SEQ ID NO:77), or Ala-Val-Lys-Lys-Tyr-X 5 (residues 1-6 of SEQ ID NO:78); Z is —CONH—, NHCO—, —S—S—, —S(CH 2 ) t CO—NH— or —NH—CO(CH 2 ) t S—; m is 1 or 2 when Z is —CONH—, —S—S— or —S(CH 2 ) t CO—NH—, or m is 2, 3 or 4 when Z is —NH—CO— or —NH—CO(CH 2 ) t S—; n is 1 or 2 when Z is —NH—CO—, —S—S— or —NH—CO(CH 2 ) t S—, or n is 2, 3 or 4 when Z is —CONH— or —S(CH 2 ) t CO—NH—, and t is 1 or 2, with the proviso that the conjugate stearoyl-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH 2 (SEQ ID NO:24) is excluded.