Scientific Publications by FDA Staff

Antioxid Redox Signal 2017 May 10;26(14):777-93

Exploring Oxidative Reactions in Hemoglobin Variants using Mass Spectrometry: Lessons for Engineering Oxidatively Stable Oxygen Therapeutics.

Strader MB, Alayash AI

SIGNIFICANCE: Worldwide demand has driven the development of hemoglobin (Hb)-based oxygen carriers (HBOCs) as potential acellular oxygen therapeutics. HBOCs have the potential to provide an oxygen bridge to patients and minimize current problems associated with supply and storage of donated blood. However, to date, safety and efficacy issues have hampered the approval of viable HBOCs in the United States. These previous efforts have underscored the need for a better molecular understanding of toxicity in order to design safe and oxidatively stable HBOCs. RECENT ADVANCES: High resolution accurate mass (HRAM) mass spectrometry (MS) has recently become a versatile tool in characterizing oxidative post translational modifications that occur in Hb. When integrated with other analytical techniques, HRAM data has been invaluable in providing mechanistic insight into the extent of oxidative modification by quantifying oxidation in amino acids near the reactive heme or at specific “oxidative hotspots”. CRITICAL ISSUES: In addition to providing a deeper understanding of Hb oxidative toxicity, HRAM MS studies are currently being employed toward developing suitable HBOCs using a “two-prong” strategy that involves: 1) understanding the mechanism of Hb toxicity by evaluating mutant Hbs identified in patients with hemoglobinopathies and 2) utilizing this information toward designing against (or for) these reactions in acellular oxygen therapeutics that will result in oxidatively stable protein. FUTURE DIRECTIONS: Future HRAM studies are aimed at fully characterizing engineered candidate HBOCs to determine which are the most oxidatively stable protein while retaining oxygen carrying function in vivo.