Peptides for heparin and low molecular weight heparin anticoagulation reversal
First Claim
1. A method of making an agent for reversing at least partially the anticoagulation effects of heparin and/or low molecular weight heparin comprising the steps of:
- preparing a synthetic peptide comprising a sequence of 20-40 uncharged and charged amino acids having a total cationic charge of less than [+21], but not lower than [+14], as determined by the number of positively charged amino acids in the sequence, the uncharged amino acids in the sequence being selected from the group consisting of glycine, glutamine, serine, threonine, asparagine, proline, valine, and isoleucine, and having the ability to at least partially reverse the effects of heparin and/or low molecular weight heparin anticoagulation; and
combining the synthetic peptide with a delivery vehicle.
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Accused Products
Abstract
Less toxic agents for reversal of heparin or low molecular weight heparin anticoagulation which are synthetic protamine-like polycationic peptides having a total cationic charge which is less than that of n-protamine. In preferred embodiments, arginine residues of n-protamine are replaced with lysine residues for ease of manufacture. Selective positively charged arginine residues have been replaced with an uncharged amino acid residue or its analog, such as glycine or glutamine, in order to reduce the total cationic charge on the polycationic peptide to the range of about [+14] to [+18], preferably [+16] to [+18]. In specific embodiments, there are sequences of 29 and 32 amino acid residues wherein 4 to 5 clusters of 2 to 4 positively charged amino acids are separated by 2 to 6 neutral amino acids. The C-terminus and the N-terminus can be modified to mitigate against in vivo degradation by carboxypeptidases and aminopeptidases. Another modification, specifically use of α-helix forming amino acids, such as glutamic acid, further promotes anticoagulation reversal.
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Citations
33 Claims
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1. A method of making an agent for reversing at least partially the anticoagulation effects of heparin and/or low molecular weight heparin comprising the steps of:
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preparing a synthetic peptide comprising a sequence of 20-40 uncharged and charged amino acids having a total cationic charge of less than [+21], but not lower than [+14], as determined by the number of positively charged amino acids in the sequence, the uncharged amino acids in the sequence being selected from the group consisting of glycine, glutamine, serine, threonine, asparagine, proline, valine, and isoleucine, and having the ability to at least partially reverse the effects of heparin and/or low molecular weight heparin anticoagulation; and combining the synthetic peptide with a delivery vehicle. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
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- 12. A method of at least partially reversing the anticoagulation effects of heparin and/or low molecular weight heparin comprising administering to a living being an anticoagulation-reversing effective amount of a synthetic peptide which is an analog of n-protamine wherein the positive charge on the amino acid sequence of n-protamine is reduced by replacement of selective positively charged arginine residues with an uncharged amino acid residue so that the total cationic charge less than [+21], but not lower than [+14], the uncharged amino acids being selected from the group consisting of glycine, glutamine, serine, threonine, asparagine, proline, valine, and isoleucine.
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15. A method of at least partially reverting the anticoagulation effects of heparin and/or low molecular weight heparin comprising the steps of:
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preparing a synthetic peptide which is an analog of n-protamine wherein the positive charge on the amino acid sequence of n-protamine is reduced by replacement of selective positively charged arginine residues with an uncharged amino acid residue so that the total cationic charge is less than [+21], but not lower than [+14]; combining the synthetic peptide with a delivery vehicle to form an anticoagulation-reversal agent; and administering to a living being an anticoagulation-reversing effective amount of the anticoagulation-reversal agent. - View Dependent Claims (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33)
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Specification