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Functional Characterization of the Nemertide alpha Family of Peptide Toxins

Jacobsson, Erik and Peigneur, Steve and Andersson, Hakan S. and Laborde, Quentin and Strand, Malin and Tytgat, Jan and Goransson, Ulf (2021). Functional Characterization of the Nemertide alpha Family of Peptide Toxins. Journal of Natural Products. 84 , 2121-2128
[Research article]

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Abstract

Peptide toxins find use in medicine, biotechnology, and agriculture. They are exploited as pharmaceutical tools, particularly for the investigation of ion channels. Here, we report the synthesis and activity of a novel family of peptide toxins: the cystine-knotted alpha nemertides. Following the prototypic alpha-1 and -2 (1 and 2), six more nemertides were discovered by mining of available nemertean transcriptomes. Here, we describe their synthesis using solid phase peptide chemistry and their oxidative folding by using an improved protocol. Nemertides alpha-2 to alpha-7 (2-7) were produced to characterize their effect on voltage-gated sodium channels (Blatella germanica BgNa(V)1 and mammalian Na(V)s1.1-1.8). In addition, ion channel activities were matched to in vivo tests using an Artemia microwell assay. Although nemertides demonstrate high sequence similarity, they display variability in activity on the tested Na(V)s. The nemertides are all highly toxic to Artemia, with EC50 values in the sub-low micromolar range, and all manifest preference for the insect BgNa(V)1 channel. Structure-activity relationship analysis revealed key residues for Na-V-subtype selectivity. Combined with low EC50 values (e.g., Na(V)1.1: 7.9 nM (alpha-6); Na(V)1.3: 9.4 nM (alpha-5); Na(V)1.4: 14.6 nM (alpha-4)) this underscores the potential utility of alpha-nemertides for rational optimization to improve selectivity.

Authors/Creators:Jacobsson, Erik and Peigneur, Steve and Andersson, Hakan S. and Laborde, Quentin and Strand, Malin and Tytgat, Jan and Goransson, Ulf
Title:Functional Characterization of the Nemertide alpha Family of Peptide Toxins
Series Name/Journal:Journal of Natural Products
Year of publishing :2021
Volume:84
Page range:2121-2128
Number of Pages:8
Publisher:AMER CHEMICAL SOC
ISSN:0163-3864
Language:English
Publication Type:Research article
Article category:Scientific peer reviewed
Version:Published version
Copyright:Creative Commons: Attribution 4.0
Full Text Status:Public
Subjects:(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 301 Basic Medicine > Pharmacology and Toxicology
(A) Swedish standard research categories 2011 > 1 Natural sciences > 106 Biological Sciences (Medical to be 3 and Agricultural to be 4) > Biochemistry and Molecular Biology
URN:NBN:urn:nbn:se:slu:epsilon-p-113599
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-p-113599
Additional ID:
Type of IDID
DOI10.1021/acs.jnatprod.1c00104
Web of Science (WoS)000692038100007
ID Code:25448
Faculty:NJ - Fakulteten för naturresurser och jordbruksvetenskap
Department:(NL, NJ) > Swedish Species Information Centre
Deposited By: SLUpub Connector
Deposited On:20 Sep 2021 07:26
Metadata Last Modified:20 Sep 2021 07:31

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