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PEGylation increases antitumoral activity of arginine deiminase of Streptococcus pyogenes.

Authors :
Schwarz R
Zitzow E
Fiebig A
Hering S
Humboldt Y
Schoenwaelder N
Kämpfer N
Volkmar K
Hinz B
Kreikemeyer B
Maletzki C
Fiedler T
Source :
Applied microbiology and biotechnology [Appl Microbiol Biotechnol] 2022 Jan; Vol. 106 (1), pp. 261-271. Date of Electronic Publication: 2021 Dec 15.
Publication Year :
2022

Abstract

Arginine auxotrophy is a metabolic defect that renders tumor cells vulnerable towards arginine-depleting substances, such as arginine deiminase (ADI) from Streptococcus pyogenes (SpyADI). Previously, we confirmed SpyADI susceptibility on patient-derived glioblastoma multiforme (GBM) models in vitro and in vivo. For application in patients, serum half-life of the enzyme has to be increased and immunogenicity needs to be reduced. For this purpose, we conjugated the S. pyogenes-derived SpyADI with 20 kDa polyethylene glycol (PEG20) moieties, achieving a PEGylation of seven to eight of the 26 accessible primary amines of the SpyADI. The PEGylation reduced the overall activity of the enzyme by about 50% without affecting the Michaelis constant for arginine. PEGylation did not increase serum stability of SpyADI in vitro, but led to a longer-lasting reduction of plasma arginine levels in mice. Furthermore, SpyADI-PEG20 showed a higher antitumoral capacity towards GBM cells in vitro than the native enzyme. KEY POINTS: • PEGylation has no effect on the affinity of SpyADI for arginine • PEGylation increases the antitumoral effects of SpyADI on GBM in vitro • PEGylation prolongs plasma arginine depletion by SpyADI in mice.<br /> (© 2021. The Author(s).)

Details

Language :
English
ISSN :
1432-0614
Volume :
106
Issue :
1
Database :
MEDLINE
Journal :
Applied microbiology and biotechnology
Publication Type :
Academic Journal
Accession number :
34910240
Full Text :
https://doi.org/10.1007/s00253-021-11728-7