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Article

Transformation of a Metal Chelate into a “Catch and Anchor” Inhibitor of Botulinum A Protease

by
Lucy Lin
1,
Ealin N. Patel
1,
Alexander L. Nielsen
1,
Lewis D. Turner
1,
William H. Tepp
2,
Kong Nguyen
3,
Sabine Pellett
2 and
Kim Janda
1,*
1
Department of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, La Jolla, CA 92037, USA
2
Department of Bacteriology, University of Wisconsin, 1550 Linden Drive, Madison, WI 53706, USA
3
Atomwise Inc., 717 Market Street, Suite 800, San Francisco, CA 94103, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(5), 4303; https://doi.org/10.3390/ijms24054303
Submission received: 28 January 2023 / Revised: 14 February 2023 / Accepted: 18 February 2023 / Published: 21 February 2023
(This article belongs to the Special Issue Advances in Clostridial and Related Neurotoxins 2.0)
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Abstract

Targeting the botulinum neurotoxin light chain (LC) metalloprotease using small-molecule metal chelate inhibitors is a promising approach to counter the effects of the lethal toxin. However, to overcome the pitfalls associated with simple reversible metal chelate inhibitors, it is crucial to investigate alternative scaffolds/strategies. In conjunction with Atomwise Inc., in silico and in vitro screenings were conducted, yielding a number of leads, including a novel 9-hydroxy-4H-pyrido [1,2-a]pyrimidin-4-one (PPO) scaffold. From this structure, an additional series of 43 derivatives were synthesized and tested, resulting in a lead candidate with a Ki of 150 nM in a BoNT/A LC enzyme assay and 17 µM in a motor neuron cell-based assay. These data combined with structure-activity relationship (SAR) analysis and docking led to a bifunctional design strategy, which we termed “catch and anchor” for the covalent inhibition of BoNT/A LC. Kinetic evaluation was conducted on structures prepared from this catch and anchor campaign, providing kinact/Ki values, and rationale for inhibition seen. Covalent modification was validated through additional assays, including an FRET endpoint assay, mass spectrometry, and exhaustive enzyme dialysis. The data presented support the PPO scaffold as a novel candidate for targeted covalent inhibition of BoNT/A LC.
Keywords: botulinum neurotoxin; catch and anchor inhibition; covalent inhibitors; structure-based drug design botulinum neurotoxin; catch and anchor inhibition; covalent inhibitors; structure-based drug design
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MDPI and ACS Style

Lin, L.; Patel, E.N.; Nielsen, A.L.; Turner, L.D.; Tepp, W.H.; Nguyen, K.; Pellett, S.; Janda, K. Transformation of a Metal Chelate into a “Catch and Anchor” Inhibitor of Botulinum A Protease. Int. J. Mol. Sci. 2023, 24, 4303. https://doi.org/10.3390/ijms24054303

AMA Style

Lin L, Patel EN, Nielsen AL, Turner LD, Tepp WH, Nguyen K, Pellett S, Janda K. Transformation of a Metal Chelate into a “Catch and Anchor” Inhibitor of Botulinum A Protease. International Journal of Molecular Sciences. 2023; 24(5):4303. https://doi.org/10.3390/ijms24054303

Chicago/Turabian Style

Lin, Lucy, Ealin N. Patel, Alexander L. Nielsen, Lewis D. Turner, William H. Tepp, Kong Nguyen, Sabine Pellett, and Kim Janda. 2023. "Transformation of a Metal Chelate into a “Catch and Anchor” Inhibitor of Botulinum A Protease" International Journal of Molecular Sciences 24, no. 5: 4303. https://doi.org/10.3390/ijms24054303

APA Style

Lin, L., Patel, E. N., Nielsen, A. L., Turner, L. D., Tepp, W. H., Nguyen, K., Pellett, S., & Janda, K. (2023). Transformation of a Metal Chelate into a “Catch and Anchor” Inhibitor of Botulinum A Protease. International Journal of Molecular Sciences, 24(5), 4303. https://doi.org/10.3390/ijms24054303

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