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

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 thera...

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Bibliographic Details
Published in:	International journal of molecular sciences Vol. 23; no. 20; p. 12096
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 11-10-2022 MDPI
Subjects:	Acetylcholine receptors (nicotinic) Amino acids Analgesics analog Analogs Animals bioassay Bioengineering Biological activity Bromination Chromatography Conotoxins Conotoxins - chemistry Conotoxins - genetics Conus Conus obscurus Conus Snail - chemistry Hydroxylation IC50 Isoforms LD50 Muscles Mutation Paralysis Peptides Peptides - metabolism Post-translation Prey Proline - metabolism Receptors, Nicotinic - genetics Receptors, Nicotinic - metabolism Residues Selectivity Toxicity Tryptophan Tryptophan - metabolism Venom Venoms α-conotoxin Conus obscurus LD50 analog milked venom α-conotoxin nAChR IC50 bioassay mass spectrometry post-translational modifications
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Summary:	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 (α-conotoxin OI) and identified the presence of α-conotoxin SI-like sequence previously found in the venom of . 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: -terminal truncation, proline hydroxylation, and tryptophan bromination. The native α-conotoxin OI demonstrated nanomolar potency in and 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 (LD ) to 18.4 (IC ) 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms232012096