title: Compstatin Cp40 blocks hematin-mediated deposition of C3b fragments on erythrocytes: Implications for treatment of malarial anemia.
abstract: During malarial anemia, 20 uninfected red blood cells (RBCs) are destroyed for every RBC infected by Plasmodium falciparum (Pf). Increasing evidence indicates an important role for complement in destruction of uninfected RBCs. Products of RBC lysis induced by Pf, including the digestive vacuole and hematin, activate complement and promote C3 fragment deposition on uninfected RBCs. C3-opsonized cells are then subject to extravascular destruction mediated by fixed tissue macrophages which express receptors for C3 fragments. The Compstatin family of cyclic peptides blocks complement activation at the C3 cleavage step, and is under investigation for treatment of complement-mediated diseases. We demonstrate, that under a variety of stringent conditions, second-generation Compstatin analogue Cp40 completely blocks hematin-mediated deposition of C3 fragments on naïve RBCs. Our findings indicate that prophylactic provision of Compstatin for malaria-infected individuals at increased risk for anemia may provide a safe and inexpensive treatment to prevent or substantially reduce malarial anemia.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, United States.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Lindorfer
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, United States.
authors.forename: Erika M
authors.initials: EM
authors.lastname: Cook
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, United States.
authors.forename: Edimara S
authors.initials: ES
authors.lastname: Reis
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricklin
authors.affiliation: Hematology, Department of Clinical Medicine and Surgery, Federico II University of Naples, Italy.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Risitano
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, United States.
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, United States. Electronic address: rpt@virginia.edu.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Taylor
mesh_terms: D000740:Anemia / Q000188:drug therapy; D003179:Complement C3b / Q000378:metabolism*; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D006427:Hemin / Q000378:metabolism*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010963:Plasmodium falciparum
chemical_list: D010456:Peptides, Cyclic; C111828:compstatin; D006427:Hemin; D003179:Complement C3b
keywords: Complement; Compstatin; Hematin; Malarial anemia