Protease resistant mutants of stromal cell derived factor-1 in the repair of tissue damage
AssigneeThe Brigham and Women's Hospital, Inc.
InventorsRichard T. LEE, Vincent SEGERS
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Abstract
The present invention is directed stromal cell derived factor-1 peptides that have been mutated to make them resistant to digestion by the proteases dipeptidyl peptidase IV (DPPIV) and matrix metalloproteinase-2 (MMP-2) but which maintain the ability of native SDF-I to attract T cells. The mutants may be attached to membranes formed by self-assembling peptides and then implanted at sites of tissue damage to help promote repair.
Claims18
1-20. (canceled)
A fusion protein comprising the formula:
- A—(L)n—(R)q, wherein:
- A is an isolated mutant form of stromal cell derived factor-1 (SDF-1) peptide comprising the formula mSDF-1 or Xp-mSDF-1, wherein mSDF-1 comprises the amino acid sequence of at least amino acids 1-8 of SEQ ID NO:52 and which is optionally extended at the C terminus of amino acids 1-8 of SEQ ID NO:
- 52 by all or any portion of the remaining sequence of SEQ ID NO:52, shown as amino acids 9-68 of the full-length of SEQ ID NO:
- 52 and the amino acids 1-8 comprises a mutation at the fourth and/or fifth amino acids from the N terminus of the amino acids 1-8 of SEQ ID NO:52, and wherein:
- a) X is a proteinogenic amino acid or a protease protective organic group;
- b) p is an integer from 1 to 4;
- and
- c) the mutant form of SDF-1 peptide has chemoattractant activity for T cells, is inactivated by dipeptidyl peptidase IV (DPPIV) at a rate that is less than one-half of the rate at which native SDF-1 is inactivated, and is inactivated by MMP-2 at a rate that is less than one-half of the rate at which native SDF-1 is inactivated;
- L is a linker sequence of 3-9 amino acids;
- R is a self-assembling peptide comprising the amino acid sequence of any one of SEQ ID NOs:
- 1-51;
- n is an integer from 0-3;
- and
- q is an integer from 1-3.
29, The fusion protein of claim 21, wherein L comprises the amino acid sequence of any one of SEQ ID NOs:
- 57-59.
The fusion protein of claim 29, wherein n is 1.
Dependencies are inferred from the claim text.