Evaluation of chemical strategies for improving the stability and oral toxicity of insecticidal peptides

Volker Herzig; A D de Araujo; K P Greenwood; Y K Y Chin; M J Windley; Y Chong; M Muttenthaler; M Mobli; N Audsley; G M Nicholson; P F Alewood; G F King

doi:10.3390/biomedicines6030090

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Evaluation of chemical strategies for improving the stability and oral toxicity of insecticidal peptides

Journal article

Open access

Peer reviewed

Evaluation of chemical strategies for improving the stability and oral toxicity of insecticidal peptides

Volker Herzig, A D de Araujo, K P Greenwood, Y K Y Chin, M J Windley, Y Chong, M Muttenthaler, M Mobli, N Audsley, G M Nicholson, …

Biomedicines, Vol.6(3), 90

2018

DOI: https://doi.org/10.3390/biomedicines6030090

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Abstract

Biochemistry and Cell Biology

Pharmacology and Pharmaceutical Sciences

insecticidal

spider venom peptide

ω-HXTX-Hv1a

oral bioavailability

diselenide bond

cyclization

selenocysteine

Spider venoms are a rich source of insecticidal peptide toxins. Their development as bioinsecticides has, however, been hampered due to concerns about potential lack of stability and oral bioactivity. We therefore systematically evaluated several synthetic strategies to increase the stability and oral potency of the potent insecticidal spider-venom peptide !-HXTX-Hv1a (Hv1a). Selective chemical replacement of disulfide bridges with diselenide bonds and N- to C-terminal cyclization were anticipated to improve Hv1a resistance to proteolytic digestion, and thereby its activity when delivered orally. We found that native Hv1a is orally active in blowflies, but 91-fold less potent than when administered by injection. Introduction of a single diselenide bond had no effect on the susceptibility to scrambling or the oral activity of Hv1a. N- to C-terminal cyclization of the peptide backbone did not significantly improve the potency of Hv1a when injected into blowflies and it led to a significant decrease in oral activity. We show that this is likely due to a dramatically reduced rate of translocation of cyclic Hv1a across the insect midgut, highlighting the importance of testing bioavailability in addition to toxin stability.

Details

Title: Evaluation of chemical strategies for improving the stability and oral toxicity of insecticidal peptides
Authors: Volker Herzig (Author) - University of Queensland
A D de Araujo (Author) - University of Queensland
K P Greenwood (Author) - University of Queensland
Y K Y Chin (Author) - University of Queensland
M J Windley (Author) - University of Technology Sydney
Y Chong (Author) - University of Technology Sydney
M Muttenthaler (Author) - University of Queensland
M Mobli (Author) - University of Queensland
N Audsley (Author)
G M Nicholson (Author) - University of Technology Sydney
P F Alewood (Author) - University of Queensland
G F King (Author) - University of Queensland
Publication details: Biomedicines, Vol.6(3), 90
Publisher: MDPI AG
Date published: 2018
DOI: 10.3390/biomedicines6030090
ISSN: 2227-9059
Copyright note: Copyright © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Organisation Unit: School of Science and Engineering - Legacy; University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
Language: English
Record Identifier: 99450967302621
Output Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Biochemistry & Molecular Biology; Medicine, Research & Experimental; Pharmacology & Pharmacy

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