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Polymer conjugation of proteins as a synthetic post-translational modification to impact their stability and activity.

ABSTRACT: For more than 40 years, protein-polymer conjugates have been widely used for many applications, industrially and biomedically. These bioconjugates have been shown to modulate the activity and stability of various proteins while introducing reusability and new activities that can be used for drug delivery, improve pharmacokinetic ability, and stimuli-responsiveness. Techniques such as RDRP, ROMP and "click" have routinely been utilized for development of well-defined bioconjugate and polymeric materials. Synthesis of bioconjugate materials often take advantage of natural amino acids present within protein and peptide structures for a host of coupling chemistries. Polymer modification may elicit increased or decreased activity, activity retention under harsh conditions, prolonged activity in vivo and in vitro, and introduce stimuli responsiveness. Bioconjugation has resulted to modulated thermal stability, chemical stability, storage stability, half-life and reusability. In this review we aim to provide a brief state of the field, highlight a wide range of behaviors caused by polymer conjugation, and provide areas of future work.

SUBMITTER: Wright TA

PROVIDER: S-EPMC6596429 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Polymer conjugation of proteins as a synthetic post-translational modification to impact their stability and activity.

Wright Thaiesha A TA Page Richard C RC Konkolewicz Dominik D

Polymer chemistry 20181207 4

For more than 40 years, protein-polymer conjugates have been widely used for many applications, industrially and biomedically. These bioconjugates have been shown to modulate the activity and stability of various proteins while introducing reusability and new activities that can be used for drug delivery, improve pharmacokinetic ability, and stimuli-responsiveness. Techniques such as RDRP, ROMP and "click" have routinely been utilized for development of well-defined bioconjugate and polymeric ma ...[more]

PMID: 31249635

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Project description:Nitric oxide ((*)NO)-derived reactive species nitrate unsaturated fatty acids, yielding nitroalkene derivatives, including the clinically abundant nitrated oleic and linoleic acids. The olefinic nitro group renders these derivatives electrophilic at the carbon beta to the nitro group, thus competent for Michael addition reactions with cysteine and histidine. By using chromatographic and mass spectrometric approaches, we characterized this reactivity by using in vitro reaction systems, and we demonstrated that nitroalkene-protein and GSH adducts are present in vivo under basal conditions in healthy human red cells. Nitro-linoleic acid (9-, 10-, 12-, and 13-nitro-9,12-octadecadienoic acids) (m/z 324.2) and nitro-oleic acid (9- and 10-nitro-9-octadecaenoic acids) (m/z 326.2) reacted with GSH (m/z 306.1), yielding adducts with m/z of 631.3 and 633.3, respectively. At physiological concentrations, nitroalkenes inhibited glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which contains a critical catalytic Cys (Cys-149). GAPDH inhibition displayed an IC(50) of approximately 3 microM for both nitroalkenes, an IC(50) equivalent to the potent thiol oxidant peroxynitrite (ONOO(-)) and an IC(50) 30-fold less than H(2)O(2), indicating that nitroalkenes are potent thiol-reactive species. Liquid chromatography-mass spectrometry analysis revealed covalent adducts between fatty acid nitroalkene derivatives and GAPDH, including at the catalytic Cys-149. Liquid chromatography-mass spectrometry-based proteomic analysis of human red cells confirmed that nitroalkenes readily undergo covalent, thiol-reversible post-translational modification of nucleophilic amino acids in GSH and GAPDH in vivo. The adduction of GAPDH and GSH by nitroalkenes significantly increased the hydrophobicity of these molecules, both inducing translocation to membranes and suggesting why these abundant derivatives had not been detected previously via traditional high pressure liquid chromatography analysis. The occurrence of these electrophilic nitroalkylation reactions in vivo indicates that this reversible post-translational protein modification represents a new pathway for redox regulation of enzyme function, cell signaling, and protein trafficking.

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Polymer conjugation of proteins as a synthetic post-translational modification to impact their stability and activity.

Publications

Polymer conjugation of proteins as a synthetic post-translational modification to impact their stability and activity.

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