Synthetic peptide derivatives that bind to fibrinogen and prevent the polymerization of fibrin monomers

Abstract

A series of small peptides corresponding to the amino termini of the [human] fibrin .alpha.- and .beta.-chains was synthesized. The peptides glycyl-L-prolyl-L-arginyl-L-proline and glycyl-L-prolyl-L-arginylsarcosine are potent inhibitors of fibrin polymerization. These peptides have a natural stability stemming from their inherent resistance to proteolysis because of the involvement of imino acids in each of their peptide bonds. The peptide glycyl-L-prolyl-L-proline binds to fibrinogen and to fragment D, in both cases with an association constant of approximately 5 .times. 104. It does not bind to fragment E. The number of binding sites is 2 for fibrinogen and 1 for fragment D. The tripeptide glycyl-L-prolyl-L-arginine binds less tightly and is less than half as effective in preventing polymerization. The peptide glycyl-L-histidyl-L-arginyl-L-proline, which corresponds exactly to the amino terminus of the fibrin .beta.-chain, does not inhibit the aggregation of fibrin monomers under the conditions used. It does bind weakly to fibrinogen, suggesting the involvement of sites other than those binding the .alpha.-chain analogues. Various other peptides did not inhibit polymerization; these included glycine-L-proline, L-prolyl-L-arginine and glycyl-L-prolyl-L-seryl-L-proline. The last-named corresponds to the serine/arginine amino acid replacement previously reported for a defective human fibrinogen.