CRFR1 selective ligands
AssigneeThe Salk Institute for Biological Studies
InventorsJean E.F. Rivier, Wylie W. Vale JR., Marilyn H. Perrin, Jozsef Gulyas
Life of this patent
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Abstract
CRF peptide analogs that bind to CRFR1 with an affinity far greater than they bind to CRFR2. These analogs exhibit CRF agonist activity.
Claims10
A 38-residue CRFR1 ligand peptide which binds to CRFR1 with an affinity substantially greater than it binds to CRFR2, which peptide has the following formula, or a nontoxic salt thereof:
- Y1-Pro-Pro-R6-Ser-R8-Asp-R10-R11-D-Phe-R13-R14-R15-Arg-R17-R18-R19-R20-R21-R22-R23-R24-R25-R26-R27-R28-R29-Gln-Glu-R32-R33-R34-Arg-R36-R37-R38-R39-R40-R41-NH2 wherein Y1 is an acyl group having not more than 15 carbon atoms or is radioiodinated tyrosine;
- R6 is Ile, Met or Nle;
- R8 is Leu or Ile;
- R10, is Leu or CML;
- R11, is Thr or Ser;
- R13 is His, Tyr or Glu;
- R14 is CML or Leu;
- R15 is CML or Leu;
- R17 is Glu, CML, Asn or Lys;
- R18 is Val, CML, Nle or Met;
- R19 is CML, Leu or Ile;
- R20 is Glu, D-Glu or His;
- R21 is Nle, Leu, CML or Met;
- R22 is Ala, D-Ala, Aib, Thr, Asp or Glu;
- R23 is Arg or Lys;
- R24 is Ala, Gln, Ile, Asn, CML or Aib;
- R25 is Asp or Glu;
- R26 is Gln, Asn or Lys;
- R27 is CML, Glu, Gln or Leu;
- R28 is Ala, Lys, Arg or Aib;
- R29 is Gln, Aib or Glu;
- R32 is Aib or an L- or D-isomer of a natural α-amino acid other than Cys;
- R33 is Aib or an L- or D-isomer of Ser, Asn, Leu, Ala, CML or Ile;
- R34 is Lys or Orn;
- R36 is Lys, Orn, Arg, Har, CML or Leu;
- R37 is CML, Leu, Nle or Tyr;
- R38 is Nle, Met, CML or Leu;
- R39 is Glu, Aib or Asp;
- R40 is Ile, Aib, CML, Thr, Glu, Ala, Val, Leu, Nle, Phe, Nva, Gly or Gln;
- and R41 is Ala, Aib, Ile, CML, Gly, Val, Leu, Nle, Phe, Nva or Gln;
- provided that a cyclizing bond may exist between Glu in position 31 and R34 and provided further that D-2Nal or D-Leu may be substituted for D-Phe.
A peptide according to claim 1 having the formula:
- (cyclo 31-34)Y1-Pro-Pro-R6-Ser-R8-Asp-Leu-R11-D-Phe-His-R14-Leu-Arg-Glu-R18-Leu-R20-Nle-R22-R23-Ala-R25-Gln-Leu-Ala-R29-Gln-Glu-R32-R33-R34-Arg-R36-R37-Nle-R39-R40-R41-NH2 wherein Y1 is an acyl group having not more than 7 carbon atoms;
- R20 is Glu or D-Glu;
- R22 is Ala or Thr;
- R29 is Gln or Glu;
- R32 is His, Aib, Ala, Gly, Leu, Gln or Glu;
- R36 is Lys or Leu;
- R37 is Leu or CML;
- R39 is Glu or Asp;
- R40 is Ile, CML or Glu;
- and R41 is Ile, Aib or Ala;
- with the remaining variables being as defined in claim 2.
A 38-residue CRFR1 ligand peptide which binds to CRFR1 with an affinity substantially greater than it binds to CRFR2, which peptide has the formula Y1-Pro-Pro-A-D-Xaa-B-Glu-Xaaa-Xaab-Xaac-C-NH2 wherein Y1 is an acyl group having not more than 15 carbon atoms or is radioiodinated tyrosine;
- A is a sequence of 6 amino acid residues that is found between Pro in the 5-position and Phe in the 12-position of r/hCRF or the corresponding sequence of another peptide of the CRF family;
- D-Xaa is D-Phe, D-2Nal or D-Leu;
- B is a sequence of 18 amino acid residues that is found between Phe in the 12-position and Ala in position-31 of r/hCRF or the corresponding sequence of another peptide of the CRF family;
- Xaaa is any L- or D-natural α-amino acid other than Cys or is Aib;
- Xaab is Aib or an L- or D-isomer of Ser, Asn, Leu, Ala, CML or Ile;
- Xaac is either Lys or Orn, the side chain of which may be linked in an amide cyclizing bond to that of Glu;
- and C is a sequence of the last 7 amino acid residues of the C-terminal portion of any peptide of the CRF family;
- provided that Nle or Leu may be substituted for Met in A, B and/or in C.
Dependencies are inferred from the claim text.