We have identified a novel heparin-like peptidyl coagulation inhibitor that is a peptide fragment of a naturally-occurring human fibrinogen isoform, gammaA/gamma' fibrinogen. The peptide is active as an anticoagulant in whole plasma, and is unlikely to elicit an immune response, since it is a normal fibrinolytic cleavage product of this fibrinogen isoform. This application focuses on the development of this peptide as a potential pharmacologic anticoagulant. This peptide anticoagulant would have significant advantages over heparin, and could be used as a general replacement for heparin, particularly when heparin is clinically contraindicated, as in cases of heparin-induced thrombocytopenia.
The specific aims are therefore to: I) Express the gamma' chain peptide in a recombinant expression system. II) Assay the recombinant gamma1,' peptide for anticoagulant and anti-platelet activities. At the conclusion of these studies, essential milestones will be achieved for Phase II development of the gamma' peptide as a pharmacologic anticoagulant.
| Lovely, Rehana S; Rein, Chantelle M; White, Tara C et al. (2008) gammaA/gamma'fibrinogen inhibits thrombin-induced platelet aggregation. Thromb Haemost 100:837-46 |
| Lovely, Rehana S; Boshkov, Lynn K; Marzec, Ulla M et al. (2007) Fibrinogen gamma'chain carboxy terminal peptide selectively inhibits the intrinsic coagulation pathway. Br J Haematol 139:494-503 |
| Flood, Veronica H; Al-Mondhiry, Hamid A; Farrell, David H (2006) The fibrinogen Aalpha R16C mutation results in fibrinolytic resistance. Br J Haematol 134:220-6 |
