A DARPin promotes faster onset of botulinum neurotoxin A1 action

Oneda Leka, Yufan Wu, Giulia Zanetti, Sven Furler, Thomas Reinberg, Joana Marinho, Jonas V. Schaefer, Andreas Plückthun, Xiaodan Li, Marco Pirazzini and Richard A. Kammerer ()
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Oneda Leka: Division of Biology, Paul Scherrer Institut
Yufan Wu: Division of Biology, Paul Scherrer Institut
Giulia Zanetti: University of Padova
Sven Furler: University of Zurich
Thomas Reinberg: University of Zurich
Joana Marinho: University of Zurich
Jonas V. Schaefer: University of Zurich
Andreas Plückthun: University of Zurich
Xiaodan Li: Division of Biology, Paul Scherrer Institut
Marco Pirazzini: University of Padova
Richard A. Kammerer: Division of Biology, Paul Scherrer Institut

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract In this study, we characterize Designed Ankyrin Repeat Proteins (DARPins) as investigative tools to probe botulinum neurotoxin A1 (BoNT/A1) structure and function. We identify DARPin-F5 that completely blocks SNAP25 substrate cleavage by BoNT/A1 in vitro. X-ray crystallography reveals that DARPin-F5 inhibits BoNT/A1 activity by interacting with a substrate-binding region between the α- and β-exosite. This DARPin does not block substrate cleavage of BoNT/A3, indicating that DARPin-F5 is a subtype-specific inhibitor. BoNT/A1 Glu-171 plays a critical role in the interaction with DARPin-F5 and its mutation to Asp, the residue found in BoNT/A3, results in a loss of inhibition of substrate cleavage. In contrast to the in vitro results, DARPin-F5 promotes faster substrate cleavage of BoNT/A1 in primary neurons and muscle tissue by increasing toxin translocation. Our findings could have important implications for the application of BoNT/A1 in therapeutic areas requiring faster onset of toxin action combined with long persistence.

Date: 2023
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DOI: 10.1038/s41467-023-44102-4

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