Chemical modification of
            <i>E. coli</i>
            <scp>L</scp>
            ‐asparaginase with polyethylene glycol grafted vinylpyrrolidone–maleic anhydride copolymer

Qian, Guoqiang; Ma, Jianbiao; Zhou, Jinchuan; He, Binglin; Wang, Daobin

doi:10.1002/(sici)1099-1581(199710)8:10<581::aid-pat689>3.0.co;2-#

Cited by 9 publications

(10 citation statements)

References 8 publications

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“…In two separate studies, Ma and co-workers 89,90 have evaluated the effect of modification of ASNase with either linear P(VP-co-MA) or comb-shaped P(MPEG 5000 -g-VP-co-MA) (MA: maleic anhydride), that is, with or without polymeric side-chains. The authors observed that the degree of protein modification required for elimination of the antigenicity of ASNase decreased as the proportion of MPEG side-chains on the comb-type polymer increased.…”

Section: Comb-type Polymer Backbonesmentioning

confidence: 99%

Polymer–protein conjugates: an enzymatic activity perspective

Gauthier¹,

2010

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Proteins have been modified with polymers in diverse manners over the past 30 years. However, while proteins have been used to prepare many functional constructs, they are sensitive biomolecules and their bioactivity can be either positively or negatively influenced by many different aspects of polymer modification. The primary focus of this review article is to highlight the opportunities offered by new trends in protein modification, and specifically how they influence the overall biological activity of the conjugate, including its dependence on temperature and pH. We survey the effect of polymer molecular weight, number of conjugated polymer chains, polymer coupling strategy (including random versus site-specific coupling, ''grafting from'', and multi-point covalent attachment), polymer architecture (including branched and comb-type), polymer interactions with the protein (including electrostatic and host-guest interactions), polymer interactions with enzyme substrate, and polymer biodegradability. We have selected six enzymes, which have been extensively modified with polymers in diverse fashions in the literature, as basis for this discussion. These proteins are L-asparaginase, alpha-chymotrypsin, trypsin, lysozyme, bovine serum albumin, and papain. This review includes polymers such as poly(ethylene glycol) (PEG), polysaccharides, polypeptides, and other synthetic (vinyl) polymers. From the discussed literature we attempt to extract tentative general trends observed between state-of-the-art methods of preparing protein-polymer conjugates and the activity of the conjugate.

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Section: Comb-type Polymer Backbonesmentioning

confidence: 99%

Polymer–protein conjugates: an enzymatic activity perspective

Gauthier¹,

2010

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“…Maleic anhydride (MA) is a reactive monomer, and the copolymers or terpolymers of MA are called reactive polymers because of the existence of MA units in the main chain. During the polymerization, anhydride units provide a reaction tendency, and these units form the active regions during graft and modification 2–4…”

Section: Introductionmentioning

confidence: 99%

“…During the polymerization, anhydride units provide a reaction tendency, and these units form the active regions during graft and modification. [2][3][4] Because of these characteristics, MA has been used in the synthesis of many copolymers and terpolymers. [5][6][7] These polymers have been used in a number of areas for various purposes.…”

Section: Introductionmentioning

confidence: 99%

Syntheses and characterization of maleic anhydride–styrene–allyl propionate terpolymer ester derivatives

Boztuğ

Basan

2003

J of Applied Polymer Sci

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ABSTRACT:In this study, maleic anhydride (MA)-styrene (St)-allyl propionate (AP) was produced with MA, St, and AP. It was then reacted with n-propyl alcohol (Pr), n-butyl alcohol (Bu), n-pentyl alcohol (Pn), and benzyl alcohol (Bz) under certain conditions to produce ester derivatives of the terpolymer. These ester derivatives were designated alkyl maleate terpolymers (PrMA-St-AP, BuMA-St-AP, PnMA-St-AP, and BzMA-St-AP). The polymers were investigated by solubility and viscosity experiments, with the number of ester groups in the polymers determined by chemical analysis. They were also characterized by Fourier transform infrared spectroscopy, with thermomechanical properties measured via stress-strain curves.

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“…We presume that the covalent crosslinking maintains the subunits within high proximity between each other, hereby facilitating the formation of the active tetrameric-structure triggered by the presence of the L-Asn substrate [ 63 , 64 ], a process that usually is rate limiting. To support these observations, we compared the catalytic activity of the 5kDa-PEG-conjugate and native non-modified enzyme at below biological temperature to introduce an energetic effect that should delay the association of the tetrameric-structure thus reducing the average catalytic activity as well [ 17 , 40 , 64 ]. At 24°C the native L-asparaginase exhibited a catalysis of 47.2 ± 1.7 U/mg, 30% of the one observed at 37°C.…”

Section: Resultsmentioning

confidence: 99%

Thiol-maleimide poly(ethylene glycol) crosslinking of L-asparaginase subunits at recombinant cysteine residues introduced by mutagenesis

et al. 2018

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L-Asparaginase is an enzyme successfully being used in the treatment of acute lymphoblastic leukemia, acute myeloid leukemia, and non-Hodgkin’s lymphoma. However, some disadvantages still limit its full application potential, e.g., allergic reactions, pancreatitis, and blood clotting impairment. Therefore, much effort has been directed at improving its performance. A popular strategy is to randomly conjugate L-asparaginase with mono-methoxy polyethylene glycol, which became a commercial FDA approved formulation widely used in recent years. To improve this formulation by PEGylation, herein we performed cysteine-directed conjugation of the L-asparaginase subunits to prevent dissociation-induced loss of activity. The recombinant cysteine conjugation sites were introduced by mutagenesis at surface-exposed positions on the protein to avoid affecting the catalytic activity. Three conjugates were obtained using different linear PEGs of 1000, 2000, and 5000 g/mol, with physical properties ranging from a semi-solid gel to a fully soluble state. The soluble-conjugate exhibited higher catalytic activity than the non-conjugated mutant, and the same activity than the native enzyme. The cysteine-directed crosslinking of the L-asparaginase subunits produced a higher molecular weight conjugate compared to the native tetrameric enzyme. This strategy might improve L-asparaginase efficiency for leukemia treatment by reducing glomerular filtration due to the increase in hydrodynamic size thus extending half-live, while at the same time retaining full catalytic activity.

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Chemical modification of E. coli L ‐asparaginase with polyethylene glycol grafted vinylpyrrolidone–maleic anhydride copolymer

Cited by 9 publications

References 8 publications

Polymer–protein conjugates: an enzymatic activity perspective

Polymer–protein conjugates: an enzymatic activity perspective

Syntheses and characterization of maleic anhydride–styrene–allyl propionate terpolymer ester derivatives

Thiol-maleimide poly(ethylene glycol) crosslinking of L-asparaginase subunits at recombinant cysteine residues introduced by mutagenesis

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