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Peptide toxins from the Antarctica: the nemertean predator and scavenger Parborlasia corrugatus
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.ORCID iD: 0000-0001-9070-6944
Karolinska Institutet, Department of Medical Biochemistry and Biophysics, 2Division of Molecular Structural Biology.ORCID iD: 0000-0003-1241-8888
University of Barcelona, Faculty of Biology, Department of Evolutionary Biology, Ecology, and Environmental Sciences, and Biodiversity Research Institute (IrBIO).
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(English)Manuscript (preprint) (Other academic)
National Category
Pharmacology and Toxicology
Research subject
Pharmacognosy; Pharmacognosy
Identifiers
URN: urn:nbn:se:uu:diva-390880OAI: oai:DiVA.org:uu-390880DiVA, id: diva2:1343019
Funder
Swedish Research Council, 2014-3327Swedish Research Council, 2018-005403Swedish Research Council Formas, 2018-00613Available from: 2019-08-15 Created: 2019-08-15 Last updated: 2019-08-15
In thesis
1. Studies on cysteine-rich peptides from Nemertea and Violaceae: Proteomic and transcriptomic discovery and characterization
Open this publication in new window or tab >>Studies on cysteine-rich peptides from Nemertea and Violaceae: Proteomic and transcriptomic discovery and characterization
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The overall aims of the projects included in this thesis were to discover, synthesize and characterize disulphide-stabilized peptides from marine worms (Nemertea sp.) and plants (Viola sp.). 

One of the main outcomes of this thesis is the discovery of a new family of highly active cysteine-rich toxins, alpha nemertides, from nemertean worms (paper II). Functional characterization and production routes of nemertides were further explored (papers II-III). In addition, 12 new cyclotides from the bog violet were discovered (paper I). Finally, transcriptomes and mucus of the Antarctic nemertean Parborlasia corrugatus were investigated for toxin content (paper IV).

 In paper I wild-type leaf and callus tissue of the endangered bog violet, V. uliginosa, were analyzed using transcriptomics and LC-MS, resulting in the discovery of 12 new cyclotides (i.e. cysteine-rich cyclic peptides). In addition, cyclotide expression under different cell-growth conditions was monitored.

In paper II  the discovery and initial characterization of a new family of highly active peptides, the alpha nemertides, from the epidermal mucus of the world’s longest animal; Lineus longissimus is described. The most abundant alpha nemertide, alpha-1, was extracted in minute amounts, prompting the use solid phase peptide synthesis (SPPS) for further characterization. The tertiary structure of alpha-1 was elucidated and revealed an inhibitory cystine knot (ICK) framework. The knotted core-structure is similar to the cyclic cystine knot (CCK) motif, found in the cyclotides described in paper I.

In manuscript III, the production route established in paper II was used to produce nemertides alpha 1-7. These were tested in vivo in an Artemia microwell assay as well as on an extended panel of voltage-gated sodium channels (NaV1.1 – 1.8 and BgNaV1). All seven alpha nemertides were highly active in the in vivo Artemia assay with EC50 values in the sub to low µM range. The alpha nemertides were also active in the NaVs tested. However, differences in the activity profiles were observed, indicating an opportunity for future optimization of alpha nemertides to reach higher specificity to certain NaV subtypes.

In manuscript IV, the exploration of nemertide toxins was extended to include the Antarctic P. corrugatus. Resulting findings include a set of cysteine-rich peptides, some similar to the nemertides previously discovered in paper II. Two purified peptides and one fraction were evaluated for their membranolytic activity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 66
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 277
Keywords
Peptide toxin, cystine knot, nemertide, cyclotide, nemertea.
National Category
Pharmacology and Toxicology
Research subject
Pharmacognosy
Identifiers
urn:nbn:se:uu:diva-390885 (URN)978-91-513-0719-0 (ISBN)
Public defence
2019-09-20, BMC A1:107a, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2019-08-30 Created: 2019-08-15 Last updated: 2019-09-17

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Jacobsson, ErikStrömstedt, Adam A.Göransson, Ulf

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