Research into the Bioengineering of a Novel α-Conotoxin from the Milked Venom of Conus obscurus

Wiere, Sean; Sugai, Christopher; Espiritu, Michael J.; Aurelio, Vincent P.; Reyes, Chloe D.; Yuzon, Nicole; Whittal, Randy M.; Tytgat, Jan; Peigneur, Steve; Bingham, Jon-Paul

doi:10.3390/ijms232012096

Open AccessArticle

Research into the Bioengineering of a Novel α-Conotoxin from the Milked Venom of Conus obscurus

by

Sean Wiere

¹,

Christopher Sugai

¹,

Michael J. Espiritu

^1,2,

Vincent P. Aurelio

¹,

Chloe D. Reyes

¹,

Nicole Yuzon

¹,

Randy M. Whittal

³,

Jan Tytgat

⁴,

Steve Peigneur

⁴

and

Jon-Paul Bingham

^1,*

¹

Department of Molecular Biosciences and Bioengineering, College of Tropical Agriculture and Human Resources, University of Hawai’i, Honolulu, HI 96822, USA

²

School of Pharmacy, Pacific University Oregon, Hillsboro, OR 97123, USA

³

Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada

⁴

Toxicology and Pharmacology, University of Leuven (KU Leuven), Campus Gasthuisberg O&N II, 3000 Leuven, Belgium

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2022, 23(20), 12096; https://doi.org/10.3390/ijms232012096

Submission received: 7 September 2022 / Revised: 4 October 2022 / Accepted: 7 October 2022 / Published: 11 October 2022

(This article belongs to the Special Issue Venoms and Ion Channels 2.0)

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Abstract

The marine cone snail produces one of the fastest prey strikes in the animal kingdom. It injects highly efficacious venom, often causing prey paralysis and death within seconds. Each snail has hundreds of conotoxins, which serve as a source for discovering and utilizing novel analgesic peptide therapeutics. In this study, we discovered, isolated, and synthesized a novel α3/5-conotoxins derived from the milked venom of Conus obscurus (α-conotoxin OI) and identified the presence of α-conotoxin SI-like sequence previously found in the venom of Conus striatus. Five synthetic analogs of the native α-conotoxin OI were generated. These analogs incorporated single residue or double residue mutations. Three synthetic post-translational modifications (PTMs) were synthetically incorporated into these analogs: N-terminal truncation, proline hydroxylation, and tryptophan bromination. The native α-conotoxin OI demonstrated nanomolar potency in Poecilia reticulata and Homosapiens muscle-type nicotinic acetylcholine receptor (nAChR) isoforms. Moreover, the synthetic α-[P9K] conotoxin OI displayed enhanced potency in both bioassays, ranging from a 2.85 (LD₅₀) to 18.4 (IC₅₀) fold increase in comparative bioactivity. The successful incorporation of PTMs, with retention of both potency and nAChR isoform selectivity, ultimately pushes new boundaries of peptide bioengineering and the generation of novel α-conotoxin-like sequences.

Keywords: α-conotoxin; analog; bioassay; IC₅₀; LD₅₀; Conus obscurus; mass spectrometry; milked venom; post-translational modifications; nAChR

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MDPI and ACS Style

Wiere, S.; Sugai, C.; Espiritu, M.J.; Aurelio, V.P.; Reyes, C.D.; Yuzon, N.; Whittal, R.M.; Tytgat, J.; Peigneur, S.; Bingham, J.-P. Research into the Bioengineering of a Novel α-Conotoxin from the Milked Venom of Conus obscurus. Int. J. Mol. Sci. 2022, 23, 12096. https://doi.org/10.3390/ijms232012096

AMA Style

Wiere S, Sugai C, Espiritu MJ, Aurelio VP, Reyes CD, Yuzon N, Whittal RM, Tytgat J, Peigneur S, Bingham J-P. Research into the Bioengineering of a Novel α-Conotoxin from the Milked Venom of Conus obscurus. International Journal of Molecular Sciences. 2022; 23(20):12096. https://doi.org/10.3390/ijms232012096

Chicago/Turabian Style

Wiere, Sean, Christopher Sugai, Michael J. Espiritu, Vincent P. Aurelio, Chloe D. Reyes, Nicole Yuzon, Randy M. Whittal, Jan Tytgat, Steve Peigneur, and Jon-Paul Bingham. 2022. "Research into the Bioengineering of a Novel α-Conotoxin from the Milked Venom of Conus obscurus" International Journal of Molecular Sciences 23, no. 20: 12096. https://doi.org/10.3390/ijms232012096

APA Style

Wiere, S., Sugai, C., Espiritu, M. J., Aurelio, V. P., Reyes, C. D., Yuzon, N., Whittal, R. M., Tytgat, J., Peigneur, S., & Bingham, J.-P. (2022). Research into the Bioengineering of a Novel α-Conotoxin from the Milked Venom of Conus obscurus. International Journal of Molecular Sciences, 23(20), 12096. https://doi.org/10.3390/ijms232012096

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Research into the Bioengineering of a Novel α-Conotoxin from the Milked Venom of Conus obscurus

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