Low oxygen affinity derivatives of human hemoglobin by fixation of polycarboxylic dextran to the oxyform.
Solutions of modified adult human hemoglobin (Hb) have potential applications as physiological oxygen carriers. The chemical modification that has been the most studied during the last few years is the cross-linking of the protein between its two alpha beta dimers, in order, first, to hamper their diffusion through the kidney and therefore increase the plasma persistence of Hb, and second, to decrease its oxygen affinity. However, despite the cross-linking, the vascular retention time is only increased by a factor of three, and a supplementary modification of cross-linked Hb is needed in order to further improve its in vivo half-life. The Hb derivatives described in this paper were obtained by the covalent fixation of benzene tetracarboxylate-substituted dextran onto oxyHb. The resulting conjugates all exhibited a higher P50 than native Hb. The experiments carried out in the presence of inositol hexaphosphate showed that the allosteric sites of Hb molecules were occupied by the polymeric reagent. The important decrease in the Bohr effect and the lack of the Cl- effect on the oxygen-binding properties proved that the Val 1 alpha residue was also substituted. Finally, the ability of some conjugates to unload as much O2 as blood, together with their other properties, make them quite promising candidates as red cell substitutes.
Prouchayret
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F
Laboratoire de Chimie-Physique Macromoléculaire, URA CNRS 494, ENSIC, Nancy, France.
Dellacherie
E
E
D000328:Adult; D002264:Carboxylic Acids / Q000737:chemistry; D003911:Dextrans / Q000737:chemistry / Q000378:metabolism*; D005404:Fixatives / Q000494:pharmacology; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism*; D010108:Oxyhemoglobins / Q000737:chemistry / Q000378:metabolism*
D002264:Carboxylic Acids; D003911:Dextrans; D005404:Fixatives; D006454:Hemoglobins; D010108:Oxyhemoglobins; D010100:Oxygen