New Modified Recombinant Botulinum Neurotoxin Type F with Enhanced Potency
Botulinum neurotoxins (BoNTs) are notorious toxins and powerful agents and can be lethal, causing botulism, but they are also widely used as therapeutics, particularly to treat neuromuscular disorders. As of today, the commercial BoNT treatments available are from native A or B serotypes. Serotype F...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | Toxins |
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| Online Access: | https://www.mdpi.com/2072-6651/13/12/834 |
| _version_ | 1797500196010065920 |
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| author | David Burgin Cindy Périer Gavin Hackett Mark Elliott Daniel Kwan Fraser Hornby Imran Mir Jacquie Maignel Sai Man Liu Matthew Beard |
| author_facet | David Burgin Cindy Périer Gavin Hackett Mark Elliott Daniel Kwan Fraser Hornby Imran Mir Jacquie Maignel Sai Man Liu Matthew Beard |
| author_sort | David Burgin |
| collection | DOAJ |
| description | Botulinum neurotoxins (BoNTs) are notorious toxins and powerful agents and can be lethal, causing botulism, but they are also widely used as therapeutics, particularly to treat neuromuscular disorders. As of today, the commercial BoNT treatments available are from native A or B serotypes. Serotype F has shown efficacy in a clinical trial but has scarcely been used, most likely due to its medium duration of effect. Previously, the uniqueness of the light chain of the F7 subtype was identified and reported, showing an extended interaction with its substrates, VAMPs 1, 2 and 3, and a superior catalytic activity compared to other BoNT/F subtypes. In order to more extensively study the properties of this neurotoxin, we engineered a modified F7 chimera, mrBoNT/F7-1, in which all the regions of the neurotoxin were identical to BoNT/F7 except the activation loop, which was the activation loop from BoNT/F1. Use of the activation loop from BoNT/F1 allowed easier post-translational proteolytic activation of the recombinant protein without otherwise affecting its properties. mrBoNT/F7-1 was expressed, purified and then tested in a suite of in vitro and in vivo assays. mrBoNT/F7-1 was active and showed enhanced potency in comparison to both native and recombinant BoNT/F1. Additionally, the safety profile remained comparable to BoNT/F1 despite the increased potency. This new modified recombinant toxin F7 could be further exploited to develop unique therapeutics to address unmet medical needs. |
| first_indexed | 2024-03-10T03:58:24Z |
| format | Article |
| id | doaj.art-c99d92ffcf0a47c4b7272dba7e441b2e |
| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-03-10T03:58:24Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-c99d92ffcf0a47c4b7272dba7e441b2e2023-11-23T10:50:11ZengMDPI AGToxins2072-66512021-11-01131283410.3390/toxins13120834New Modified Recombinant Botulinum Neurotoxin Type F with Enhanced PotencyDavid Burgin0Cindy Périer1Gavin Hackett2Mark Elliott3Daniel Kwan4Fraser Hornby5Imran Mir6Jacquie Maignel7Sai Man Liu8Matthew Beard9Ipsen Bioinnovation, 102 Park Drive, Abingdon OX14 3YS, UKIpsen Innovation, 5 Avenue du Canada, 91940 Les Ulis, FranceIpsen Bioinnovation, 102 Park Drive, Abingdon OX14 3YS, UKIpsen Bioinnovation, 102 Park Drive, Abingdon OX14 3YS, UKIpsen Bioinnovation, 102 Park Drive, Abingdon OX14 3YS, UKIpsen Bioinnovation, 102 Park Drive, Abingdon OX14 3YS, UKIpsen Bioinnovation, 102 Park Drive, Abingdon OX14 3YS, UKIpsen Innovation, 5 Avenue du Canada, 91940 Les Ulis, FranceIpsen Bioinnovation, 102 Park Drive, Abingdon OX14 3YS, UKIpsen Bioinnovation, 102 Park Drive, Abingdon OX14 3YS, UKBotulinum neurotoxins (BoNTs) are notorious toxins and powerful agents and can be lethal, causing botulism, but they are also widely used as therapeutics, particularly to treat neuromuscular disorders. As of today, the commercial BoNT treatments available are from native A or B serotypes. Serotype F has shown efficacy in a clinical trial but has scarcely been used, most likely due to its medium duration of effect. Previously, the uniqueness of the light chain of the F7 subtype was identified and reported, showing an extended interaction with its substrates, VAMPs 1, 2 and 3, and a superior catalytic activity compared to other BoNT/F subtypes. In order to more extensively study the properties of this neurotoxin, we engineered a modified F7 chimera, mrBoNT/F7-1, in which all the regions of the neurotoxin were identical to BoNT/F7 except the activation loop, which was the activation loop from BoNT/F1. Use of the activation loop from BoNT/F1 allowed easier post-translational proteolytic activation of the recombinant protein without otherwise affecting its properties. mrBoNT/F7-1 was expressed, purified and then tested in a suite of in vitro and in vivo assays. mrBoNT/F7-1 was active and showed enhanced potency in comparison to both native and recombinant BoNT/F1. Additionally, the safety profile remained comparable to BoNT/F1 despite the increased potency. This new modified recombinant toxin F7 could be further exploited to develop unique therapeutics to address unmet medical needs.https://www.mdpi.com/2072-6651/13/12/834botulinum neurotoxinrecombinant proteinpotencysafety profilein vivo |
| spellingShingle | David Burgin Cindy Périer Gavin Hackett Mark Elliott Daniel Kwan Fraser Hornby Imran Mir Jacquie Maignel Sai Man Liu Matthew Beard New Modified Recombinant Botulinum Neurotoxin Type F with Enhanced Potency Toxins botulinum neurotoxin recombinant protein potency safety profile in vivo |
| title | New Modified Recombinant Botulinum Neurotoxin Type F with Enhanced Potency |
| title_full | New Modified Recombinant Botulinum Neurotoxin Type F with Enhanced Potency |
| title_fullStr | New Modified Recombinant Botulinum Neurotoxin Type F with Enhanced Potency |
| title_full_unstemmed | New Modified Recombinant Botulinum Neurotoxin Type F with Enhanced Potency |
| title_short | New Modified Recombinant Botulinum Neurotoxin Type F with Enhanced Potency |
| title_sort | new modified recombinant botulinum neurotoxin type f with enhanced potency |
| topic | botulinum neurotoxin recombinant protein potency safety profile in vivo |
| url | https://www.mdpi.com/2072-6651/13/12/834 |
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