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Functional Characterization of the Nemertide α Family of Peptide Toxins
[Image: see text] 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 α nemertides. Fol...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society and American Society of Pharmacognosy
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406415/ https://www.ncbi.nlm.nih.gov/pubmed/34445875 http://dx.doi.org/10.1021/acs.jnatprod.1c00104 |
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author | Jacobsson, Erik Peigneur, Steve Andersson, Håkan S. Laborde, Quentin Strand, Malin Tytgat, Jan Göransson, Ulf |
author_facet | Jacobsson, Erik Peigneur, Steve Andersson, Håkan S. Laborde, Quentin Strand, Malin Tytgat, Jan Göransson, Ulf |
author_sort | Jacobsson, Erik |
collection | PubMed |
description | [Image: see text] 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 α nemertides. Following the prototypic α-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 α-2 to α-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 EC(50) 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 EC(50) values (e.g., Na(V)1.1: 7.9 nM (α-6); Na(V)1.3: 9.4 nM (α-5); Na(V)1.4: 14.6 nM (α-4)) this underscores the potential utility of α-nemertides for rational optimization to improve selectivity. |
format | Online Article Text |
id | pubmed-8406415 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Chemical Society and American Society of Pharmacognosy |
record_format | MEDLINE/PubMed |
spelling | pubmed-84064152021-09-01 Functional Characterization of the Nemertide α Family of Peptide Toxins Jacobsson, Erik Peigneur, Steve Andersson, Håkan S. Laborde, Quentin Strand, Malin Tytgat, Jan Göransson, Ulf J Nat Prod [Image: see text] 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 α nemertides. Following the prototypic α-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 α-2 to α-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 EC(50) 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 EC(50) values (e.g., Na(V)1.1: 7.9 nM (α-6); Na(V)1.3: 9.4 nM (α-5); Na(V)1.4: 14.6 nM (α-4)) this underscores the potential utility of α-nemertides for rational optimization to improve selectivity. American Chemical Society and American Society of Pharmacognosy 2021-08-16 2021-08-27 /pmc/articles/PMC8406415/ /pubmed/34445875 http://dx.doi.org/10.1021/acs.jnatprod.1c00104 Text en © 2021 The Authors. Published by American Chemical Society and American Society of Pharmacognosy https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Jacobsson, Erik Peigneur, Steve Andersson, Håkan S. Laborde, Quentin Strand, Malin Tytgat, Jan Göransson, Ulf Functional Characterization of the Nemertide α Family of Peptide Toxins |
title | Functional Characterization of the Nemertide α
Family of Peptide Toxins |
title_full | Functional Characterization of the Nemertide α
Family of Peptide Toxins |
title_fullStr | Functional Characterization of the Nemertide α
Family of Peptide Toxins |
title_full_unstemmed | Functional Characterization of the Nemertide α
Family of Peptide Toxins |
title_short | Functional Characterization of the Nemertide α
Family of Peptide Toxins |
title_sort | functional characterization of the nemertide α
family of peptide toxins |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406415/ https://www.ncbi.nlm.nih.gov/pubmed/34445875 http://dx.doi.org/10.1021/acs.jnatprod.1c00104 |
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