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Dextrin-trypsin and ST-HPMA-trypsin conjugates: Enzyme activity, autolysis and thermal stability

Treetharnmathurot, Benjaporn, Dieudonné, L., Ferguson, Elaine ORCID:, Schmaljohann, Dirk, Duncan, Ruth and Wiwattanapatapee, R. 2009. Dextrin-trypsin and ST-HPMA-trypsin conjugates: Enzyme activity, autolysis and thermal stability. International Journal of Pharmaceutics 373 (1-2) , pp. 68-76. 10.1016/j.ijpharm.2009.02.008

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Using monomethoxy poly(ethylene glycol) (mPEG)-trypsin conjugates we recently showed that both PEG molecular weight (1100-5000 g/mol) and linker chemistry affect the rate of protein autolysis and thermal stability. These important factors are often overlooked but they can guide the early choice of optimal polymer/chemistry for synthesis of a lead polymer therapeutic suitable for later formulation development. As we are currently developing dextrin- and semi-telechelic poly[N-(2-hydroxypropyl)methacrylamide] (ST-HPMA)-protein conjugates as new therapeutics, the aim of this study was to examine the effect of polymer on activity, autolysis and its thermal stability using trypsin conjugates as a model and compare to the data obtained for mPEG conjugates. Trypsin conjugates were first synthesized using succinoylated dextrin (Mw ∼ 8000 g/mol, dextrin I; or ∼61,000 g/mol, dextrin II), and a ST-HPMA-COOH (Mw ∼ 10,100 g/mol). The conjugates had a trypsin content of ∼54, 17 and 3 wt% respectively with <5% free protein. When amidase activity (KM, Vmax and Kcat) was determined by using N-benzoyl-l-arginine p-nitroanilide (BAPNA) as substrate, trypsin KM values were not altered by conjugation, but the Vmax was ∼6-7-fold lower, and the substrate turnover rate (Kcat) decreased by ∼5-7-fold. The dextrin II-trypsin conjugate was more stable than the other conjugates and native trypsin at all temperatures between 30 and 70 °C, and also exhibited improved thermal stability in the autolysis assays at 40 °C. © 2009 Elsevier B.V. All rights reserved.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Subjects: R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: dextrin; semi-telechelic poly[n-(2-hydroxypropyl)methacrylamide]; polymer–protein conjugates; thermal stability; trypsin; polymer therapeutics
Publisher: Elsevier
ISSN: 0378-5173
Last Modified: 18 Oct 2022 13:59

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