Melanocortin metallopeptide constructs, combinatorial libraries and applications
AssigneePalatin Technologies, Inc.
InventorsShubh D. Sharma, Yiqun Shi, Wei Yang, Hui-Zhi Cai
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Abstract
Metallopeptides and metallopeptide combinatorial libraries specific for melanocortin receptors are provided, for use in biological, pharmaceutical and related applications. The metallopeptides and combinatorial libraries are made of peptides, peptidomimetics and peptide-like constructs, in which the peptide, peptidomimetic or construct is conformationally fixed on complexation of a metal ion-binding portion thereof with a metal ion.
Claims54
A manufactured peptide and pharmaceutically acceptable salts thereof comprising a metal ion-binding domain comprising two or more contiguous amino acids and a biological-function domain specific for one or more melanocortin receptors and a metal ion selected from the group consisting of rhenium and technetium complexed to the metal ion-binding domain, wherein at least a portion of said biological-function domain is co-extensive with at least a portion of the metal ion-binding domain, and wherein said biological-function domain is conformationally constrained upon complexing the metal ion-binding domain with a metal ion, and wherein the peptide or salt thereof is substantially more specific for one or more melanocortin receptors when the metal ion-binding domain is complexed with a metal ion than is the peptide or salt thereof when the metal ion-binding domain is not complexed with a metal ion, wherein the peptide is of the formulas:
- R1-Lll-Aaa-Bbb-Ccc-R2,
- R1-Bbb-Aaa-Ccc-R2,
- R1-Ddd-Bbb-Aaa-R3,
- R4-Eee-Bbb-Ccc-R2,
- R1-Hhh-Aaa-Bbb-Ccc-R5, or
- R1-Iii-Iii-Ccc-Jjj-Kkk-R2,
- wherein
- R1 comprises a functionality that potentiates the intrinsic activity of the remainder of the peptide, including but not limited to providing an auxiliary or secondary receptor contact;
- Aaa is an L- or D-configuration cationic amino acid with a positively charged side chain;
- Bbb is an L- or D-configuration amino acid with an aromatic side chain;
- Ccc is an amino acid that provides both a nitrogen atom (N), from the alpha amino group, and a sulfur atom (S), from a side chain group, for metal ion complexation;
- Lll is a D-configuration amino acid with an aromatic side chain;
- R2 is optionally present, and if present, comprises an amino acid with an aromatic side chain;
- Ddd is an amino acid that provides an S, from a side chain group, for metal ion complexation;
- R3 is an amino acid with an aromatic side chain that provides an N for metal ion complexation;
- R4 is a functionality that provides a cationic center;
- Eee is an uncharged L- or D-configuration amino acid that provides an N for metal ion complexation:
- R5 is an amide, substituted amide, ester or carboxylate group, or comprises an L- or D-configuration amino acid;
- Hhh is an L- or D-configuration cationic amino acid with a positively charged side chain;
- Iii is an L- or D-configuration amino acid that provides an N for metal ion complexation;
- Jjj is an L- or D-configuration amino acid with an aromatic side chain;
- and
- Kkk is an L- or D-configuration cationic amino acid with a positively charged side chain.
A manufactured peptide and pharmaceutically acceptable salts thereof comprising a metal ion-binding domain comprising two or more contiguous amino acids and a biological-function domain specific for one or more melanocortin receptors and a metal ion selected from the group consisting of rhenium and technetium complexed to the metal ion-binding domain, wherein at least a portion of said biological-function domain is co-extensive with at least a portion of the metal ion-binding domain, and wherein said biological-function domain is conformationally constrained upon complexing the metal ion-binding domain with a metal ion, and wherein the peptide or salt thereof is substantially more specific for one or more melanocortin receptors when the metal ion-binding domain is complexed with a metal ion than is the peptide or salt thereof when the metal ion-binding domain is not complexed with a metal ion, wherein the peptide is of the formula:
- R1-Fff-Aaa-Ggg-Ccc-R5,
- wherein
- R1 comprises a functionality that potentiates the intrinsic activity of the remainder of the peptide, including but not limited to providing an auxiliary or secondary receptor contact;
- Aaa is an L- or D-configuration cationic amino acid with a positively charged side chain;
- Ccc is an amino acid that provides both a nitrogen atom (N), from the alpha amino group, and a sulfur atom (S), from a side chain group, for metal ion complexation;
- Fff is an L- or D-configuration aromatic amino acid wherein the aromatic ring of the aromatic side chain of Fff is substituted with halogen, alkyl or aryl groups or is a D-configuration Phe, Phe(4′Cl), Phe(3′,4′ Di-Cl), Phe(4′-nitro), Phe(4′-methyl), Phe(4′-Phenyl), Hphe, Pgl, Trp, 1-Nal, 2-Nal, Ser(Bzl), Lys(Z), Lys(Z-2′Br), Lys(Bz), Thr(Bzl), Cys(Bzl), Tyr(BzlCl2), Tic, Tiq or Tca, or derivative, analog or homolog thereof;
- Ggg is an L- or D-configuration aromatic amino acid;
- and
- R5 is an amide, substituted amide, ester or carboxylate group, or comprises an L- or D-configuration amino acid.
A manufactured peptide and pharmaceutically acceptable salts thereof comprising a metal ion-binding domain comprising two or more contiguous amino acids and a biological-function domain specific for one or more melanocortin receptors and a metal ion selected from the group consisting of rhenium and technetium complexed to the metal ion-binding domain, wherein at least a portion of said biological-function domain is co-extensive with at least a portion of the metal ion-binding domain, and wherein said biological-function domain is conformationally constrained upon complexing the metal ion-binding domain with a metal ion, and wherein the peptide or salt thereof is substantially more specific for one or more melanocortin receptors when the metal ion-binding domain is complexed with a metal ion than is the peptide or salt thereof when the metal ion-binding domain is not complexed with a metal ion, wherein the peptide is of the formula:
- R1-Fff-Aaa-Ggg-Ccc-R5,
- wherein
- R1 comprises a functionality that potentiates the intrinsic activity of the remainder of the peptide, including but not limited to providing an auxiliary or secondary receptor contact;
- Aaa is an L- or D-configuration cationic amino acid with a positively charged side chain;
- Ccc is an amino acid that provides both a nitrogen atom (N), from the alpha amino group, and a sulfur atom (S), from a side chain group, for metal ion complexation;
- Fff is an L- or D-configuration aromatic amino acid;
- Ggg is an L- or D-configuration aromatic amino acid wherein the aromatic ring of the aromatic side chain of Ggg is substituted with halogen, alkyl or aryl groups or is an L-configuration Phe, Phe(4′Cl), Phe(3′,4′ Di-Cl), Phe(4′-nitro), Phe(4′-methyl), Phe(4′-Phenyl), Hphe, Pgl, 1-Nal, 2-Nal, Ser(Bzl), Lys(Z), Lys(Z-2′Br), Lys(Bz), Thr(Bzl), Cys(Bzl) or Tyr(BzlCl2), and derivatives, analogs or homologs thereof, including both natural and synthetic amino acids;
- and
- R5 is an amide, substituted amide, ester or carboxylate group, or comprises an L- or D-configuration amino acid.
Dependencies are inferred from the claim text.