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US 6,723,694 B1Granted
Short peptides which selectively modulate intracellular signalling
AssigneesChildren's Medical Center Corporation, Yissum Research Development Company of the Hebrew University of Jerusalem
InventorShmuel A. Ben-Sasson
Life of this patent
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Abstract
Disclosed are peptides which are peptide derivatives of the HJ loop of a protein tyrosine kinase. The peptides can modulate the activity of the protein tyrosine kinase. Also disclosed are methods of modulating the activity of a protein tyrosine kinase in a subject by administering one of the peptides of the present invention.
Claims87
A peptide capable of modulating the activity of a protein tyrosine kinase having a structure that includes the twelve subdomains and nine alpha helices that are characteristic of the protein tyrosine kinase superfamily, consisting of:
- (a) a subsequence of an HJ-loop peptide, which subsequence consists of at least five contiguous amino acids of said HJ-loop peptide, and which subsequence peptide modulates the activity of the protein tyrosine kinase of which said HJ-loop peptide is a part, wherein said HJ-loop peptide is a peptide consisting of a sequence of about 20 amino acid residues of the protein tyrosine kinase between the middle of Subdomain IX and the middle of Subdomain X, beginning about five residues from the N-terminus of the F helix and extending to about five amino acid residues into the G helix, which amino acids correspond to a continuous stretch of the prototypical PKA-Cα in positions 229-248 of the PKA-Cα, and which HJ-loop peptide modulates the activity of the protein tyrosine kinase;
- (b) a modified sequence peptide having a modified sequence of (a) in which up to two residues are each substituted by another amino acid residue or amino acid residue analog, which modified sequence peptide modulates the activity of the protein tyrosine kinase;
- (c) a protected peptide (a) or (b) in which the N-terminus and/or the C-terminus is protected by a protecting group, which protected peptide modulates the activity of the protein tyrosine kinase;
- or
- (d) a cyclized peptide of (a), (b), or (c) which has been cyclized, which cyclized peptide modulates the activity of the protein tyrosine kinase.
2 more elements
A peptide having the sequence of a peptide selected from the group consisting of HJ4 (SEQ ID NO.:
- 13), HJ4.2 (SEQ ID NO.:
- 14), HJ4Nitro (SEQ ID NO.:
- 15), HJ6 (SEQ ID NO.:
- 16), HJ7 (SEQ ID NO.:
- 17), HJ7.1 (SEQ ID NO.:
- 18), HJ8 (SEQ ID NO.:
- 19), HJ9 (SEQ ID NO.:
- 20), HJ10 (SEQ ID NO.:
- 21), HJ11 (SEQ ID NO.:
- 22), HJ11.1 (SEQ ID NO.:
- 23), HJ11Met (SEQ ID NO.:
- 24), HJ12 (SEQ ID NO.:
- 25), HJ13 (SEQ ID NO.:
- 26), HJ14 (SEQ ID NO.:
- 27), HJ15 (SEQ ID NO.:
- 28), HJ18 (SEQ ID NO.:
- 29), HJ20, (SEQ ID NO.:
- 30), HJ20.1 (SEQ ID NO.:
- 31), HJ21.1 (SEQ ID NO.:
- 32), HJ22 (SEQ ID NO.:
- 33), HJ23.1 (SEQ ID NO.:
- 34), HJ24 (SEQ ID NO.:
- 1), HJ25 (SEQ ID NO.:
- 35), HJ27 (SEQ ID NO.:
- 36), HJ28 (SEQ ID NO.:
- 37), HJ29 (SEQ ID NO.:
- 48), HJ30 (SEQ ID NO.:
- 38), HJ31 (SEQ ID NO.:
- 39), HJ32 (SEQ ID NO.:
- 2), HJ33 (SEQ ID NO.:
- 40), HJ34 (SEQ ID NO.:
- 41), HJ40 (SEQ ID NO.:
- 47), Lena 1 (SEQ ID NO.:
- 42), Lena 2 (SEQ ID NO.:
- 43) and J29 (SEQ ID NO.:
- 44), with the proviso that any one amino acid residue in the peptide can be substituted by another amino acid residue or amino acid residue analog.
33 more elements
A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
- AA1 is threonine or tryptophan;
- AA2 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA3 is selected from the group consisting of leucine, isoleucine, methionine and valine;
- AA4 is selected from the group consisting of methionine, threonine, serine, valine, isoleucine and leucine;
- AA5 is threonine or serine;
- AA6 is selected from the group consisting of ornithine, lysine, histidine, tyrosine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyargine, N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
- AA7 is glycine or alanine;
- AA8 is selected from the group consisting of arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyargine, N-amidinocitruline, 2-amino-4-guanidinobutanoic acid and lysine;
- AA9 is selected from the group consisting of valine, isoleucine, leucine and methionine;
- AA10 is proline;
- AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
- AA12 is proline;
- AA13 is glycine or alanine;
- AA14 is selected from the group consisting of methionine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyargine, N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
- AA15 is selected from the group consisting of valine, asparagine, threonine and serine;
- AA16 is asparagine or lysine;
- AA17 is selected from the group consisting of arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyargine, N-amidinocitruline, 2-amino-4-guanidinobutanoic acid alanine, and proline;
- AA18 is selected from the group consisting of glutamine, asparagine, glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA19 is selected from the group consisting of valine, isoleucine, leucine and methionine;
- and
- AA20 is selected from the group consisting of leucine, isoleucine, methionine and valine.
18 more elements
A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
- AA1 is tryptophan;
- AA2 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benxyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA3 is selected from the group consisting of valine, leucine, isoleucine and methionine;
- AA4 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
- AA5 is threonine or serine;
- AA6 is tyrosine, phenylalanine or tryptophan;
- AA7 is glycine or alanine;
- AA8 is selected from the group consisting of arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyargine, N-amidinocitruline, 2-amino-4-guanidinobutanoic acid, ornithine, and lysine;
- AA9 is valine or alanine;
- AA10 is proline;
- AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
- AA12 is proline;
- AA13 is selected from the group consisting of ornithine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyargine, N-amidinocitruline, 2-amino-4-guanidinobutanoic acid and lysine;
- AA14 is selected from the group consisting of valine, methionine, isoleucine and leucine;
- AA15 is selected from the group consisting of proline, threonine and serine;
- AA16 is selected from the group consisting of leucine, isoleucine, valine and methionine;
- AA17 is selected from the group consisting of ornithine, lysine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyargine, N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
- AA18 is selected from the group consisting of asparagine, glutamine, glutamic acid, aspartic acid, and an aliphatic, substituted aliphatic, benzyl, substituted benzyl or substituted aromatic ester of aspartic acid or glutamic acid;
- AA19 is selected from the group consisting of valine, isoleucine, leucine and methionine;
- and
- AA20 is selected from the group consisting of leucine, isoleucine, methionine and valine.
18 more elements
A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
- AA1 is tryptophan;
- AA2 is glutamic acid or an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or aromatic ester of glutamic acid;
- AA3 is selected from the group consisting of isoleucine, leucine, alanine and methionine;
- AA4 is selected from the group consisting of alanine, glycine and valine;
- AA5 is threonine or serine;
- AA6 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
- AA7 is glycine or alanine;
- AA8 is selected from the group consisting of methionine, valine, leucine and isoleucine;
- AA9 is serine or threonine;
- AA10 is proline;
- AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
- AA12 is proline;
- AA13 is glycine or alanine;
- AA14 is selected from the group consisting of methionine, isoleucine, valine and leucine;
- AA15 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA16 is selected from the group consisting of leucine, isoleucine, proline, lysine, ornithine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyarginine, N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
- AA17 is serine or threonine;
- AA18 is selected from the group consisting of glutamine, asparagine, glutamicacid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA19 is selected from the group consisting of valine, isoleucine, leucine and methionine;
- and
- AA20 is selected from the group consisting of tyrosine, phenylalanine and tryptophan.
18 more elements
A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
- AA1 is tryptophan;
- AA2 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA3 is selected from the group consisting of leucine, isoleucine, valine and methionine;
- AA4 is selected from the group consisting of methionine, leucine, isoleucine and valine;
- AA5 is threonine or serine;
- AA6 is selected from the group consisting of tyrosine, lysine, arginine, ornithine, N-nitroarginine, β-cycloarginine, γ-hydroxyarginine, N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
- AA7 is glycine or alanine;
- AA8 is glycine or alanine;
- AA9 is selected from the group consisting of proline, serine and threonine;
- AA10 is proline;
- AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
- AA12 is proline;
- AA13 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA14 is selected from the group consisting of valine, methionine, isoleucine and leucine;
- AA15 is selected from the group consisting of glutamine, asparagine, glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA16 is threonine or proline;
- AA17 is selected from the group consisting of phenylalanine, tyrosine and tryptophan;
- AA18 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA19 is selected from the group consisting of valine, isoleucine, leucine and methionine;
- and
- AA20 is selected from the group consisting of threonine, serine and C-agitated derivatives thereof.
18 more elements
A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
- AA1 is tryptophan;
- AA2 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA3 is selected from the group consisting of leucine, isoleucine, methionine and valine;
- AA4 is selected from the group consisting of methionine, leucine, isoleucine and valine;
- AA5 is selected from the group consisting of methionine, valine, isoleucine and leucine;
- AA6 is selected from the group consisting of histidine, lysine and ornithine;
- AA7 is glycine or alanine;
- AA8 is selected from the group consisting of valine, alanine and glycine;
- AA9 is selected from the group consisting of lysine, ornithine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyarginine, N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
- AA10 is proline;
- AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
- AA12 is glutamine or proline;
- AA13 is glycine or alanine;
- AA14 is selected from the group consisting of valine, isoleucine, leucine and alanine;
- AA15 is selected from the group consisting of lysine, ornithine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyarginine, N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
- AA16 is selected from the group consisting of glutamine, asparagine, glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA17 is selected from the group consisting of glutamine, asparagine, glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of aspartic acid and glutamic acid;
- AA18 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA19 is selected from the group consisting of valine, isoleucine, leucine and methionine;
- and
- AA20 is selected from the group consisting of valine, isoleucine, leucine, methionine and C-agitated derivatives thereof.
18 more elements
A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
- AA1 is tryptophan or methionine;
- AA2 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA3 is selected from the group consisting of leucine, isoleucine, methionine and valine;
- AA4 is selected from the group consisting of methionine, valine, isoleucine and leucine;
- AA5 is threonine or serine;
- AA6 is selected from the group consisting of phenylalanine, tyrosine and tryptophan;
- AA7 is glycine or alanine;
- AA8 is selected from the group consisting of arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyarginine, N-amidinocitruline, 2-amino-4-guanidinobutanoic acid, lysine and ornithine;
- AA9 is selected from the group consisting of valine, isoleucine, leucine and methionine;
- AA10 is proline;
- AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
- AA12 is proline;
- AA13 is glycine or alanine;
- AA14 is selected from the group consisting of methionine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyarginine , N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
- AA15 is threonine or serine;
- AA16 is asparagine or glutamine;
- AA17 is selected from the group consisting of alanine, glycine and proline;
- AA18 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA19 is selected from the group consisting of valine, isoleucine, leucine and methionine;
- and
- AA20 is selected from the group consisting of leucine, isoleucine, methionine and valine.
18 more elements
A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
- AA1 is tryptophan;
- AA2 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA3 is selected from the group consisting of leucine, isoleucine, methionine and valine;
- AA4 is selected from the group consisting of phenylalanine, tyrosine and tryptophan;
- AA5 is threonine or serine;
- AA6 is selected from the group consisting of leucine, isoleucine, valine and methionine;
- AA7 is glycine or alanine;
- AA8 is glycine or alanine;
- AA9 is serine or threonine;
- AA10 is proline;
- AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
- AA12 is selected from the group consisting of proline, cysteine, serine and alanine;
- AA13 is glycine or alanine;
- AA14 is selected from the group consisting of rmethionine, valine, isoleucine and leucine;
- AA15 is selected from the group consisting of serine, threonine, methionine, proline, lysine, ornithine, glutamine and asparagine;
- AA16 is selected from the group consisting of cysteine, serine, methionine, valine, isoleucine and leucine;
- AA17 is selected from the group consisting of alanine, asparagine, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of aspartic acid;
- AA18 is selected from the group consisting of threonine, serine, glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA19 is selected from the group consisting of threonine, leucine, glutamine, asparagine, glutamic acid, aspartic acid and an aliphatic substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- and
- AA20 is selected from the group consisting of tyrosine, phenylalanine and tryptophan.
18 more elements
A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
- AA1 is tryptophan;
- AA2 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA3 is selected from the group consisting of leucine, isoleucine, methionine and valine;
- AA4 is selected from the group consisting of phenylalanine, tyrosine and tryptophan;
- AA5 is threonine or serine;
- AA6 is selected from the group consisting of phenylalanine, tyrosine and tryptophan;
- AA7 is glycine or alanine;
- AA8 is lsyine or ornithine;
- AA9 is glutamine or asparagine;
- AA10 is proline;
- AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
- AA12 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
- AA13 is glutamine or asparagine;
- AA14 is selected from the group consisting of leucine, isoleucine, methionine and valine;
- AA15 is serine or threonine;
- AA16 is glutamine or asparagine;
- AA17 is threonine or asparagine;
- AA18 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA19 is selected from the group consisting of glycine, alanine and valine;
- and
- AA20 is selected from the group consisting of leucine, isoleucine, methionine and valine.
18 more elements
A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
- AA1 is glutamic acid, aspartic acid or an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA2 is leucine, isoleucine, methionine or valine;
- AA3 is serine, threonine or proline;
- AA4 is phenylalanine, tyrosine or tryptophan;
- AA5 is glutamic acid, aspartic acid or an aliphatic, substituted aliphatic, benzyl, substituted-benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA6 is leucine, isoleucine, methionine or valine;
- AA7 is leucine, isoleucine, methionine or valine;
- AA8 is threonine or serine;
- AA9 is phenylalanine, tyrosine or tryptophan;
- AA10 is glycine or alanine;
- AA11 is serine, alanine, threonine or glycine;
- AA12 is lysine, ornithine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyarginine, N-amidinocitruline or 2-amino-4-guanidinobutanoic acid;
- AA13 is proline;
- AA14 is tyrosine, phenylalanine or tryptophan;
- AA15 is glutamic acid, aspartic acid or an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
- AA16 is glycine or alanine;
- AA17 is leucine, isoleucine, methionine or valine;
- AA18 is proline;
- AA19 is glycine, alanine, serine or threonine;
- and
- AA20 is serine, arginine, N-nitroarginine β-cycloarginine, γ-hydroxyarginine, N-amidinocitruline or 2-amino-4-guanidinobutanoic acid.
18 more elements
A protected or cyclized peptide capable of modulating the activity of a protein tyrosine kinase having a structure that includes the twelve subdomains and nine alpha helices that are characteristic of the protein tyrosine kinase superfamily, consisting of:
- (a) an HJ-loop peptide consisting of a sequence of about 20 amino acid residues of the protein tyrosine kinase between the middle of Subdomain IX and the middle of Subdomain X, beginning about five residues from the N-terminus of the F helix and extending to about five amino acid residues into the G helix, which amino acids correspond to a continuous stretch of the prototypical PKA-Cα in positions 229-248 of the PKA-Cα, and which HJ-loop peptide modulates the activity of the protein tyrosine kinase;
- (b) a subsequence peptide consisting of a subsequence of (a) consisting of at least five contiguous amino acids thereof, which subsequence peptide modulates the activity of the protein tyrosine kinase;
- or
- (c) a modified sequence peptide having a modified sequence of (a) or (b) in which up to two residues are each substituted by another amino acid residue or amino acid residue analog, which modified sequence peptide modulates the activity of the protein tyrosine kinase;
- which peptide of (a), (b) or (c) is (1) a protected peptide in which the N-terminus and/or the C-terminus is protected by a protecting group which facilitates transport of the peptide into a cell, which protected peptide modulates the activity of the protein tyrosine kinase, or
- which peptide of (a), (b) or (c) or said protected peptide is (2) a cyclized peptide in which said peptide of (a), (b) or (c) or said protected peptide has been cyclized, which cyclized peptide modulates the activity of the protein tyrosine kinase.
3 more elements
A cyclized peptide in accordance with cliam 60, wherein said peptide which is cyclized consists of a subsequence peptide of (b).
A method of modulating activity of a protein tyrosine kinase in a subject, comprising administering a therapeutically effective amount of a peptide capable of modulating the activity of a protein tyrosine kinase having a structure that includes the twelve subdomains and nine alpha helices that are characteristic of the protein tyrosine kinase superfamily, consisting of:
- (a) an HJ-loop peptide consisting of a sequence of about 20 amino acid residues of the protein tyrosine kinase between the middle of Subdomain IX and the middle of Subdomain X, beginning about five residues from the N-terminus of the F helix and extending to about five amino acid residues into the G helix, which amino acids correspond to a continuous stretch of the prototypical PKA-Cα in positions 229-248 of the PKA-Cα, and which HJ-loop peptide modulates the activity of the protein tyrosine kinase;
- (b) a subsequence peptide consisting of a subsequence of (a) consisting of at least five contiguous amino acids thereof, which subsequence peptide modulates the activity of the protein tyrosine kinase;
- (c) a modified sequence peptide having a modified sequence of (a) or (b) in which up to two residues are each substituted by another amino acid residue or amino acid residue analog, which modified sequence peptide modulates the activity of the protein tyrosine kinase;
- (d) a protected peptide (a), (b) or (c) in which the N-terminus and/or the C-terminus is protected by a protecting group, which protected peptide modulates the activity of the protein tyrosine kinase;
- or
- (e) a cyclized peptide of (a), (b), (c) or (d) which has been cyclized, which cyclized peptide modulates the activity of the protein tyrosine kinase.
3 more elements
Dependencies are inferred from the claim text.