Comprehensive Biochemical and Biophysical Characterization of Hemoglobin-Based Oxygen Carrier Therapeutics: All HBOCs Are Not Created Equally,Bioconjugate Chemistry

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Comprehensive Biochemical and Biophysical Characterization of Hemoglobin-Based Oxygen Carrier Therapeutics: All HBOCs Are Not Created Equally
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-03-23 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00093
Fantao Meng ₁ , Tigist Kassa ₁ , Sirsendu Jana ₁ , Francine Wood ₁ , Xiaoyuan Zhang ₁ , Yiping Jia ₁ , Felice D’Agnillo ₁ , Abdu I. Alayash ₁

Affiliation

The development of hemoglobin (Hb)-based oxygen carriers (HBOCs) has been hampered because of safety concerns in humans. Chemical and/or genetic modifications of the Hb introduce varied structural and conformational constraint on the molecule that resulted in proteins with diverse allosteric responses, nitrosative and oxidative side reactions. Here, we present for the first time a comprehensive biochemical and biophysical comparison of human, bovine, and genetically engineered HBOCs that have been tested in humans. We evaluate oxygen equilibrium and ligand binding kinetics under different experimental conditions as well as their autoxidation kinetics, redox reactions, and heme release. We determined the effects of HBOCs on cellular redox states and mitochondrial respiration. Taken together, these experiments provide a better understanding of the relationship between the structure–function and oxidative reactivity of these proteins. One can therefore select independently among these diverse properties to engineer a safe and effective HBOC with improved biochemical/biophysical characteristics.

中文翻译：

基于血红蛋白的氧气载体疗法的全面生化和生物物理表征：并非平等地创建所有HBOC

由于对人体的安全性考虑，阻碍了基于血红蛋白（Hb）的氧载体（HBOC）的开发。Hb的化学和/或遗传修饰在分子上引入了不同的结构和构象约束，从而导致蛋白质具有多种变构反应，亚硝化和氧化副反应。在这里，我们首次展示了经过人类测试的人类，牛和基因工程HBOC的全面生化和生物物理比较。我们评估了不同实验条件下的氧平衡和配体结合动力学，以及它们的自氧化动力学，氧化还原反应和血红素释放。我们确定了HBOCs对细胞氧化还原状态和线粒体呼吸的影响。在一起这些实验提供了对这些蛋白质的结构功能与氧化反应性之间关系的更好理解。因此，人们可以在这些不同的属性中独立选择，以设计出具有改良的生化/生物物理特性的安全有效的HBOC。

更新日期：2018-03-23

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