Gla-domainless activated protein C

GED-aPC (Gla-domainless activated protein C) is an engineered, recombinant form of human activated protein C (aPC) designed to decouple its cytoprotective signaling from its anticoagulant properties. In its wild-type form, aPC requires an N-terminal gamma-carboxyglutamic acid (Gla) domain to bind to negatively charged phospholipids on cell membranes, a step necessary for the proteolytic inactivation of coagulation factors Va and VIIIa. By removing this Gla domain, GED-aPC loses its ability to function as an anticoagulant, thereby significantly reducing the risk of hemorrhage—a major side effect that led to the withdrawal of the wild-type aPC drug, drotrecogin alfa (Xigris). Despite the lack of a Gla domain, GED-aPC retains high-affinity binding to the endothelial protein C receptor (EPCR) and can subsequently cleave and activate protease-activated receptors 1 and 3 (PAR1 and PAR3). This signaling pathway initiates a variety of beneficial cellular responses, including stabilization of the blood-brain barrier, anti-apoptotic effects in neurons and endothelial cells, and suppression of pro-inflammatory cytokines. Developed primarily at the Scripps Research Institute, GED-aPC has been extensively studied in preclinical models of ischemic stroke, sepsis, and other inflammatory conditions as a safer alternative to wild-type aPC for therapeutic cytoprotection.

Other names

Gla-domainless APCdes-Gla APCGla-domain-deleted activated protein C