Peptide-derivatized albumins that inhibit fibrin polymerization.
Synthetic peptides patterned on sequences that appear during thrombin proteolysis of fibrinogen are known to influence fibrin formation in very different ways. A-Knob sequences (GPR-) inhibit polymerization, but B-knob sequences (GHR-) can actually enhance the process. We now report that when such peptides are attached to albumin carriers, both knob conjugates inhibit fibrin formation. In contrast, the 2-aminoethylthiol-albumin conjugate control enhances the polymerization to the same degree as albumin. The peptide AHRPam, which is known to bind exclusively to the βC holes of fibrinogen/fibrin, nullifies the inhibitory effects of the GHRPYGGGCam-albumin conjugate on fibrin polymerization, indicating that the inhibition was exclusively due to interactions with βC holes. AHRPam was much less effective in countering inhibition by the GPRPGGGGCam-albumin conjugate, suggesting that the observed effects with this conjugate involve mainly the γC holes of fibrin/fibrinogen. This study demonstrates that peptides modeled on fibrin polymerization knobs tethered to albumin retain their capacity to interact with fibrinogen/fibrin and may prove useful as inhibitors of clotting in vivo.
Department of Chemistry and Biochemistry and Division of Biology, University of California, San Diego, La Jolla, California 92093-0314, United States.
Joseph W
JW
Watson
Russell F
RF
Doolittle
D000418:Albumins / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D005337:Fibrin / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry; D010455:Peptides / Q000737:chemistry* / Q000235:genetics; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D059748:Proteolysis
D000418:Albumins; D046912:Multiprotein Complexes; D010455:Peptides; D005337:Fibrin