‘Messy’ Processing of χ-conotoxin MrIA Generates Homologues with Reduced hNET Potency
Integrated venomics techniques have shown that variable processing of conotoxins from Conus marmoreus resulted in a dramatic expansion in the number of expressed conotoxins. One conotoxin from C. marmoreus, the χ-conotoxin MrIA, is a selective inhibitor of human norepinephrine transporters (...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-03-01
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| Series: | Marine Drugs |
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| Online Access: | http://www.mdpi.com/1660-3397/17/3/165 |
| _version_ | 1817990788396613632 |
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| author | Rebekah Ziegman Andreas Brust Prerna Jha Fernanda C. Cardoso Richard J. Lewis Paul F. Alewood |
| author_facet | Rebekah Ziegman Andreas Brust Prerna Jha Fernanda C. Cardoso Richard J. Lewis Paul F. Alewood |
| author_sort | Rebekah Ziegman |
| collection | DOAJ |
| description | Integrated venomics techniques have shown that variable processing of conotoxins from Conus marmoreus resulted in a dramatic expansion in the number of expressed conotoxins. One conotoxin from C. marmoreus, the χ-conotoxin MrIA, is a selective inhibitor of human norepinephrine transporters (hNET) and therefore a drug candidate for attenuating chronic neuropathic pain. It has been found that “messy” processing of the MrIA transcripts results in the expression of MrIA analogs with different truncations of the pro-peptide that contains portions of the MrIA molecule. The aim of this study was to investigate if variable processing of the expressed peptides results in modulation of the existing hNET pharmacology or creates new pharmacologies. To this end, a number of MrIA analogs found in C. marmoreus venom were synthesized and evaluated for their activity at hNET receptors. While several of the analogs exhibited norepinephrine transporter inhibitory activity comparable to that of MrIA, none significantly improved on the potency of conotoxin MrIA, and those analogs with disrupted pharmacophores produced greatly reduced NET inhibition, confirming previous structure-activity relationships seen on χ-class conopeptides. Additionally, analogs were screened for new activities on ion channels using calcium influx assays, although no major new pharmacology was revealed. |
| first_indexed | 2024-04-14T01:04:41Z |
| format | Article |
| id | doaj.art-b2965d419ce54b3f907b4ef487788751 |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-04-14T01:04:41Z |
| publishDate | 2019-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-b2965d419ce54b3f907b4ef4877887512022-12-22T02:21:18ZengMDPI AGMarine Drugs1660-33972019-03-0117316510.3390/md17030165md17030165‘Messy’ Processing of χ-conotoxin MrIA Generates Homologues with Reduced hNET PotencyRebekah Ziegman0Andreas Brust1Prerna Jha2Fernanda C. Cardoso3Richard J. Lewis4Paul F. Alewood5Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, AustraliaInstitute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, AustraliaInstitute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, AustraliaInstitute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, AustraliaInstitute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, AustraliaInstitute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, AustraliaIntegrated venomics techniques have shown that variable processing of conotoxins from Conus marmoreus resulted in a dramatic expansion in the number of expressed conotoxins. One conotoxin from C. marmoreus, the χ-conotoxin MrIA, is a selective inhibitor of human norepinephrine transporters (hNET) and therefore a drug candidate for attenuating chronic neuropathic pain. It has been found that “messy” processing of the MrIA transcripts results in the expression of MrIA analogs with different truncations of the pro-peptide that contains portions of the MrIA molecule. The aim of this study was to investigate if variable processing of the expressed peptides results in modulation of the existing hNET pharmacology or creates new pharmacologies. To this end, a number of MrIA analogs found in C. marmoreus venom were synthesized and evaluated for their activity at hNET receptors. While several of the analogs exhibited norepinephrine transporter inhibitory activity comparable to that of MrIA, none significantly improved on the potency of conotoxin MrIA, and those analogs with disrupted pharmacophores produced greatly reduced NET inhibition, confirming previous structure-activity relationships seen on χ-class conopeptides. Additionally, analogs were screened for new activities on ion channels using calcium influx assays, although no major new pharmacology was revealed.http://www.mdpi.com/1660-3397/17/3/165conotoxinMrIApeptidesNorepinephrine Transporter Inhibitor (NET)bioactivity |
| spellingShingle | Rebekah Ziegman Andreas Brust Prerna Jha Fernanda C. Cardoso Richard J. Lewis Paul F. Alewood ‘Messy’ Processing of χ-conotoxin MrIA Generates Homologues with Reduced hNET Potency Marine Drugs conotoxin MrIA peptides Norepinephrine Transporter Inhibitor (NET) bioactivity |
| title | ‘Messy’ Processing of χ-conotoxin MrIA Generates Homologues with Reduced hNET Potency |
| title_full | ‘Messy’ Processing of χ-conotoxin MrIA Generates Homologues with Reduced hNET Potency |
| title_fullStr | ‘Messy’ Processing of χ-conotoxin MrIA Generates Homologues with Reduced hNET Potency |
| title_full_unstemmed | ‘Messy’ Processing of χ-conotoxin MrIA Generates Homologues with Reduced hNET Potency |
| title_short | ‘Messy’ Processing of χ-conotoxin MrIA Generates Homologues with Reduced hNET Potency |
| title_sort | messy processing of χ conotoxin mria generates homologues with reduced hnet potency |
| topic | conotoxin MrIA peptides Norepinephrine Transporter Inhibitor (NET) bioactivity |
| url | http://www.mdpi.com/1660-3397/17/3/165 |
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