Peptides for heparin and low molecular weight heparin anticoagulation

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 .alpha.-helix forming amino acids, such as glutamic acid, further promotes anticoagulation reversal. A still further modification includes the incorporation of a cell adhesion ligand, such as the RGD sequence, into the synthetic protamine-like polycationic peptide.