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

Herzig, V; de Araujo, AD; Greenwood, KP; Chin, YKY; Windley, MJ; Chong, Y; Muttenthaler, M; Mobli, M; Audsley, N; Nicholson, GM; Alewood, PF; King, GF

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

Herzig, V de Araujo, AD Greenwood, KP Chin, YKY Windley, MJ Chong, Y Muttenthaler, M Mobli, M Audsley, N Nicholson, GM

Alewood, PF King, GF

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Publication Type:: Journal Article
Citation:: Biomedicines, 2018, 6 (3)
Issue Date:: 2018-09-01

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Field	Value	Language
dc.contributor.author	Herzig, V	en_US
dc.contributor.author	de Araujo, AD	en_US
dc.contributor.author	Greenwood, KP	en_US
dc.contributor.author	Chin, YKY	en_US
dc.contributor.author	Windley, MJ	en_US
dc.contributor.author	Chong, Y	en_US
dc.contributor.author	Muttenthaler, M	en_US
dc.contributor.author	Mobli, M	en_US
dc.contributor.author	Audsley, N	en_US
dc.contributor.author	Nicholson, GM https://orcid.org/0000-0002-4277-4296	en_US
dc.contributor.author	Alewood, PF	en_US
dc.contributor.author	King, GF https://orcid.org/0000-0002-2308-2200	en_US
dc.date.available	2018-08-23	en_US
dc.date.issued	2018-09-01	en_US
dc.identifier.citation	Biomedicines, 2018, 6 (3)	en_US
dc.identifier.uri	http://hdl.handle.net/10453/127505
dc.description.abstract	© 2018 by the authors. 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.	en_US
dc.relation	http://purl.org/au-research/grants/arc/DP0559396
dc.relation	http://purl.org/au-research/grants/arc/LX0775899
dc.relation.ispartof	Biomedicines	en_US
dc.relation.isbasedon	10.3390/biomedicines6030090	en_US
dc.title	Evaluation of chemical strategies for improving the stability and oral toxicity of insecticidal peptides	en_US
dc.type	Journal Article
utslib.citation.volume	3	en_US
utslib.citation.volume	6	en_US
utslib.for	0305 Organic Chemistry	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	open_access
pubs.issue	3	en_US
pubs.publication-status	Published	en_US
pubs.volume	6	en_US

Abstract:

© 2018 by the authors. 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.

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http://hdl.handle.net/10453/127505