US 2003/0152564 A1Published application

Anti-inflammatory peptides derived from C-reactive protein

AssigneeYeda Research and Development Co. Ltd. at the Weizmann Institute of Science

InventorsMatityahu Fridkin, Eran Yavin

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Abstract

A peptide corresponding to positions 62-71 of the sequence of human C-reactive protein (CRP) of the formula: Glu62-Ile-Leu-Ile-Phe-Trp-Ser-Lys-Asp-Ile71 and modifications thereof obtained by substitution, deletion, or addition of amino acids, amidation of the C-terminal or acylation of the N-terminal, are capable of inhibiting in vitro the enzymatic activity of human Leukocyte Elastase (hLE) and/or of human Cathepsin G (hCG) and can be used for the treatment of chronic inflammation conditions such as rheumatoid arthritis, pulmonary emphysema, cystic fibrosis, bronchitis, asthma and some acute respiratory distress syndrome.

Claims2

Dependent claims

A method for the treatment of a chronic inflammatory condition which comprises administering to a patient in need thereof an effective amount of a peptide capable of inhibiting in vitro the enzymatic activity of human Leukocyte Elastase (hLE) and/or of human Cathepsin G (hCG), said peptide being selected from the group consisting of:

(i) a core peptide corresponding to positions 62-71 of the sequence of human C-reactive protein (CRP) of the formula:
Glu62-Ile-Leu-Ile-Phe-Trp-Ser-Lys-Asp-Ile71 (residues 62-71 of SEQ ID NO:
1)
or peptides resulting from modification thereof characterized by:
(ii) substitution of Glu62 by Asp or by a non-amino acid negatively charged residue derived from succinic, glutaric or adipic acids;
(iii) substitution of any of the residues Ile63, Leu64, Ile65, Phe66 or Trp67 by a natural or non-natural hydrophobic amino acid residue;
(iv) deletion of 1 or 2 amino acid residues selected from the group consisting of Ile63, Leu64, Ile65, Phe66 and Trp67;
(v) substitution of 1-3 amino acid residues selected from the group consisting of Ile63, Leu64, Ile65, Phe66 and Trp67 by a single non-natural amino acid residue derived from 6-aminocaproic acid;
(vi) substitution of 2-4 amino acid residues selected from the group consisting of Ile63, Leu64, Ile65, Phe66 and Trp67 by a single non-natural amino acid residue derived from 8-aminocaproic acid or 10-aminodecanoic acid;
(vii) substitution of 3-5 amino acid residues selected from the group consisting of Ile63, Leu64, Ile65, Phe66 and Trp67 by a stretch of identical hydrophobic amino acid residues or by a single non-natural amino acid residue derived from 10-aminodecanoic acid or 12-aminolauric acid;
(viii) substitution of Ser68 by a natural or non-natural amino acid residue selected from the group consisting of Thr, Cys, Ala and homoserine;
(ix) substitution of Lys69 by a natural or non-natural positively charged or hydrophobic amino acid residue;
(x) substitution of Asp70 by a negatively charged or a polar amino acid residue selected from the group consisting of Glu, Asn or Gln;
(xi) substitution of Ile71 by a natural or non-natural hydrophobic amino acid residue;
(xii) elongation of a peptide (i) to (xi) by 1-5 non-charged amino acid residues at the N-terminus and/or at the C-terminus;
(xiii) substitution of any amino acid residue in a peptide (i) to (xii) by the corresponding N-alkyl derivative, D-amino acid residue or by another isoster;
(xiv) an amide of the C-terminal of a peptide (i) to (xiii);
and
(xv) an N-acyl derivative of a peptide (i) to (xiv).

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Dependencies are inferred from the claim text.

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Abstract

(i) a core peptide corresponding to positions 62-71 of the sequence of human C-reactive protein (CRP) of the formula:
Glu62-Ile-Leu-Ile-Phe-Trp-Ser-Lys-Asp-Ile71 (residues 62-71 of SEQ ID NO:
1)
or peptides resulting from modification thereof characterized by:
(ii) substitution of Glu62 by Asp or by a non-amino acid negatively charged residue derived from succinic, glutaric or adipic acids;
(iii) substitution of any of the residues Ile63, Leu64, Ile65, Phe66 or Trp67 by a natural or non-natural hydrophobic amino acid residue;
(iv) deletion of 1 or 2 amino acid residues selected from the group consisting of Ile63, Leu64, Ile65, Phe66 and Trp67;
(v) substitution of 1-3 amino acid residues selected from the group consisting of Ile63, Leu64, Ile65, Phe66 and Trp67 by a single non-natural amino acid residue derived from 6-aminocaproic acid;
(vi) substitution of 2-4 amino acid residues selected from the group consisting of Ile63, Leu64, Ile65, Phe66 and Trp67 by a single non-natural amino acid residue derived from 8-aminocaproic acid or 10-aminodecanoic acid;
(vii) substitution of 3-5 amino acid residues selected from the group consisting of Ile63, Leu64, Ile65, Phe66 and Trp67 by a stretch of identical hydrophobic amino acid residues or by a single non-natural amino acid residue derived from 10-aminodecanoic acid or 12-aminolauric acid;
(viii) substitution of Ser68 by a natural or non-natural amino acid residue selected from the group consisting of Thr, Cys, Ala and homoserine;
(ix) substitution of Lys69 by a natural or non-natural positively charged or hydrophobic amino acid residue;
(x) substitution of Asp70 by a negatively charged or a polar amino acid residue selected from the group consisting of Glu, Asn or Gln;
(xi) substitution of Ile71 by a natural or non-natural hydrophobic amino acid residue;
(xii) elongation of a peptide (i) to (xi) by 1-5 non-charged amino acid residues at the N-terminus and/or at the C-terminus;
(xiii) substitution of any amino acid residue in a peptide (i) to (xii) by the corresponding N-alkyl derivative, D-amino acid residue or by another isoster;
(xiv) an amide of the C-terminal of a peptide (i) to (xiii);
and
(xv) an N-acyl derivative of a peptide (i) to (xiv).

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