Our long-term goal is to develop for the safe, effective treatment of sickle cell anemia. Our approach involves the rational design and selection, synthesis and testing of stereospecific inhibitors of sickle cell hemoglogin (HbS) polymerization (gelling). To do this, we follow an iterative, cyclic process which involves: (1) using structural information and basic chemical principles to (re-)design compounds to bind to specific sites on Hb, or to select such compounds from among FDA-approved drugs used for other purposes; (2) syntehsizing designed or selected compounds and analogs of these compounds; (3) testing the synthetic compounds for antigelllng activity and effect on oxygen equilibrium; (4) performing X-ray crystallographic studies of the compounds bound to Hb to obtain structural information on binding sites, binding site environments and binding characteristics for use in the next iteration of the cycle. Red cell permetion, rheological, toxicological and in vivo distribution studies are done on the most active compounds. The proposed work builds upon and will extend our past successes achieved through oru use of this process.
Its specific aims are to: (1) determine the covalent bindings site of ethacrynic acid on Hb; (2) test ethacrynic acid analogs which do not have a diuretic effect; (3) synthesize analogs of highly active compounds in our phenoxy and benzyloxy series to improve binding affinity; (4) determine the binding sites on Hb of active meta disubstituted benzoic acid derivatives; (5) determine the physiological effects of binding of various compounds at various sites on Hb; (6) test compounds developed or selected for antigelling activity and oxygen equlibrium effects, and perform red cell permeation, solution binding, rheological and toxicological studies of the most active compounds. In vivo distribution studies of radio-labeled analogs of the most active compounds will be done by colleagues at no cost to the project. Results of this work should greatly further progress toward our ultimate goal of developing drugs for the safe, effective treatment of sickle cell anemia.
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