Detection and characterization of altered conformations of protein pharmaceuticals using complementary mass spectrometry-based approaches.

Analytical Chemistry
Cedric E BobstIgor A Kaltashov

Abstract

Unlike small-molecule drugs, the conformational properties of protein biopharmaceuticals in solution are influenced by a variety of factors that are not solely defined by their covalent chemical structure. Since the conformation (or higher order structure) of a protein is a major modulator of its biological activity, the ability to detect changes in both the higher order structure and conformational dynamics of a protein, induced by an array of extrinsic factors, is of central importance in producing, purifying, and formulating a commercial biopharmaceutical with consistent therapeutic properties. In this study we demonstrate that two complementary mass spectrometry-based approaches (analysis of ionic charge-state distribution and hydrogen/deuterium exchange) can be a potent tool in monitoring conformational changes in protein biopharmaceuticals. The utility of these approaches is demonstrated by detecting and characterizing conformational changes in the biopharmaceutical product interferon beta-1a (IFN-beta-1a). The protein degradation process was modeled by inducing a single chemical modification of IFN-beta1a (alkylation of its only free cysteine residue with N-ethylmaleimide), which causes significant reduction in its antiv...Continue Reading

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Citations

Mar 1, 2012·Analytical and Bioanalytical Chemistry·José González-ValdezJorge Benavides
Dec 8, 2009·Journal of the American Society for Mass Spectrometry·Igor A KaltashovDamian Houde
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