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Complementarity determining regions of an anti-prion protein scFv fragment orchestrate conformation specificity and antiprion activity

Title data

Müller-Schiffmann, Andreas ; Petsch, Benjamin ; Leliveld, S. Rutger ; Muyrers, Janine ; Salwierz, Agnieska ; Mangels, Christian ; Schwarzinger, Stephan ; Riesner, Detlev ; Stitz, Lothar ; Korth, Carsten:
Complementarity determining regions of an anti-prion protein scFv fragment orchestrate conformation specificity and antiprion activity.
In: Molecular Immunology. Vol. 46 (2009) Issue 4 . - pp. 532-540.
ISSN 0161-5890
DOI: https://doi.org/10.1016/j.molimm.2008.07.023

Official URL: Volltext

Abstract in another language

The prion protein, PrP, exists in several stable conformations, with the presence of one conformation, PrPSc, associated with transmissible neurodegenerative diseases. Targeting PrP by high-affinity ligands has been proven to be an effective way of preventing peripheral prion infections. Here, we have generated bacterially expressed single chain fragments of the variable domains (scFv) of a monoclonal antibody in Escherichia coli, originally raised against purified PrPSc that recognizes both PrPC and PrPSc. This scFv fragment had a dissociation constant (KD) with recombinant PrP of 2 nM and cleared prions in ScN2a cells at 4 nM, as demonstrated by a mouse prion bioassay. A peptide corresponding to the complementarity determining region 3 of the heavy chain (CDR3H) selectively bound PrPSc but had lost antiprion activity. However, synthesis and application of an improved peptide mimicking side chain topology of CDR3H while exhibiting increased protease resistance, a retro-inverso d-peptide of CDR3H, still bound PrPSc and reinstated antiprion activity. We conclude that (1) scFvW226 is so far the smallest polypeptide with bioassay confirmed antiprion activity, and (2) differential conformation specificity and bioactivity can be regulated by orchestrating the participation of different CDRs.

Further data

Item Type: Article in a journal
Refereed: Yes
Keywords: Prions, Monoclonal antibody, Conformation specificity, Complementarity determining regions, Recombinant antibodies, Retro-inverso d-peptides
Institutions of the University: Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biopolymers
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Former Professors > Chair Biopolymers - Univ.-Prof. Dr. Paul Rösch
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Former Professors
Result of work at the UBT: Yes
DDC Subjects: 500 Science
500 Science > 500 Natural sciences
500 Science > 540 Chemistry
500 Science > 570 Life sciences, biology
Date Deposited: 19 Dec 2014 07:52
Last Modified: 08 Dec 2015 06:41
URI: https://eref.uni-bayreuth.de/id/eprint/5096