Prevention of complement-mediated immune hemolysis by a small molecule compound.
Complement sensitization of red blood cells (RBCs) can result in transfusion reactions and hemolytic anemias. We hypothesized that manipulating the complement system using small organic molecules might prevent RBC destruction, thereby prolonging RBC survival in patients. Using a simple, rapid, large-scale hemolytic assay, we screened a 10,000 compound library, enriched in anti-inflammatory compounds at a final concentration of 25 microM, and identified a 549Da compound (C(34)H(24)N(6)O(2)) with a symmetrical structure containing two benzimidazole rings that, as compared to a known anti-complement molecule FUT-175, was more effective in reducing hemolysis by the classical pathway and had comparable anti-hemolytic activity against the alternative pathway. Furthermore, in a xenotransfusion mouse model, treatment of mice with 1.2mg/kg of the compound significantly prolonged the survival of transfused RBCs, reducing C3 deposition, but not the deposition of control IgG or IgM, for the first hour post-transfusion. These data suggest that further studies are warranted to determine if this compound has usefulness in a transfusion setting.
Mqadmi
Amina
A
Complement Biology, New York Blood Center, 310, E 67th Street, New York, NY 10021, USA.
Zheng
Xiaoying
X
Song
Jinmei
J
Abramowitz
Steven
S
Giclas
Patricia
P
Yazdanbakhsh
Karina
K
D000743:Anemia, Hemolytic / Q000276:immunology* / Q000517:prevention & control*; D000818:Animals; D001803:Blood Transfusion; D003167:Complement Activation / Q000187:drug effects; D015941:Complement Hemolytic Activity Assay / Q000379:methods*; D003165:Complement System Proteins / Q000187:drug effects / Q000276:immunology*; D006461:Hemolysis / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009930:Organic Chemicals / Q000276:immunology* / Q000494:pharmacology; D019151:Peptide Library
D009930:Organic Chemicals; D019151:Peptide Library; D003165:Complement System Proteins