A protease-resistant Escherichia coli asparaginase with outstanding stability and enhanced anti-leukaemic activity in vitro

Scientific Reports
Maristella MaggiClaudia Scotti

Abstract

L-Asparaginases (ASNases) have been used as first line drugs for paediatric Acute Lymphoblastic Leukaemia (ALL) treatment for more than 40 years. Both the Escherichia coli (EcAII) and Erwinia chrysanthemi (ErAII) type II ASNases currently used in the clinics are characterized by high in vivo instability, short half-life and the requirement of several administrations to obtain a pharmacologically active concentration. Moreover, they are sensitive to proteases (cathepsin B and asparagine endopeptidase) that are over-expressed by resistant leukaemia lymphoblasts, thereby impairing drug activity and pharmacokinetics. Herein, we present the biochemical, structural and in vitro antiproliferative characterization of a new EcAII variant, N24S. The mutant shows completely preserved asparaginase and glutaminase activities, long-term storage stability, improved thermal parameters, and outstanding resistance to proteases derived from leukaemia cells. Structural analysis demonstrates a modification in the hydrogen bond network related to residue 24, while Normal Mode-based geometric Simulation and Molecular Dynamics predict a general rigidification of the monomer as compared to wild-type. These improved features render N24S a potential alte...Continue Reading

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Citations

Aug 20, 2019·Protein Science : a Publication of the Protein Society·Jacek Lubkowski, Alexander Wlodawer
Sep 26, 2019·World Journal of Microbiology & Biotechnology·Angela Beckett, David Gervais
Jan 29, 2019·Frontiers in Bioengineering and Biotechnology·Larissa Pereira BrumanoAdalberto Pessoa Junior
May 3, 2019·British Journal of Haematology·Ilaria M MichelozziMarta Serafini
Aug 1, 2019·Scientific Reports·Jacek LubkowskiAlexander Wlodawer
Feb 20, 2021·Biophysical Chemistry·Talita Stelling de AraújoLuís Maurício T R Lima
Aug 14, 2020·Biochemistry·Ashish RadadiyaNigel G J Richards
May 1, 2021·Pharmaceutics·Cristina Díaz-BarrigaAlejandro Huerta-Saquero
May 2, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Marcela Helena Gambim FonsecaRaphael Trevizani
Jun 2, 2021·The FEBS Journal·Jacek Lubkowski, Alexander Wlodawer

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Methods Mentioned

BETA
thermal shift
PISA
deamidation
PCR
restriction digest
electrophoresis
X-ray

Software Mentioned

Normal Mode NMSim
Magtran
PISA
DiscoTope
SCALA
SPSS
ElliPro
- REFINE
LIGAND FIT
Oncaspar

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