IMIDOESTERS AS ANTISICKLING AGENTS

GENERALLY, OXYGEN AFFINITY INCREASES AFTER TREATMENT OF HEMOGLOBIN S (HBS) WITH COVALENT ANTISICKLING AGENTS, SUCH AS IMIDOESTER CROSSLINKING REAGENTS. ADDING INOSITOL HEXAPHOSPHATE (IHP) DURING THE CROSSLINKING PROCEDURE WILL LOWER THE AFFINITY, PROTECT THE 2,3-DIPHOSPHOGLYCERATE BINDING SITE AND ULTIMATELY IMPROVE OXYGEN DELIVERY TO TISSUES. THE GOAL OF THIS PROJECT IS TO PRODUCE A STABLE HBS THAT WILL NOT AGGREGATE UPON DEOXYGENATION AND HAS AN OXYGEN AFFINITY SIMILAR TO HEMOGLOBIN A IN NORMAL BLOOD. TO ACCOMPLISH THIS GOAL HBS WILL BE SYSTEMATICALLY CROSSLINKED IN THE PRESENCE OF IHP WITH VARIOUS IMIDOESTERS HAVING CHAIN LENGTHS FROM ONE TO EIGHT CARBON ATOMS. THE OPTIMUM REAGENT WOULD BE USED TO TREAT RBC EXTRACORPOREALLY IN PHASE II. SUCH A TREATMENT, THAT MAXIMALLY INHIBITS POLYMERIZATION, WITH LITTLE OR NO CHANGE IN THE INTRINSIC OXYGEN AFFINITY OF THE HBS MOLECULE, WOULD IMPROVE THE CLINICIANS ABILITY TO MANAGE SICKLE CELL PATIENTS. FURTHERMORE, AUTOLOGOUS TRANSFUSIONS OF ERYTHROCYTES TREATED EXTRACORPOREALLY WOULD REDUCE MORBIDITY AND MORTALITY ASSOCIATED WITH THE DISEASE AS WELL AS REDUCE THE INFECTIOUS AND IMMUNOLOGIC COMPLICATIONS ASSOCIATED WITH DONOR DERIVED BLOOD TRANSFUSIONS.