کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8394305 | 1544089 | 2018 | 29 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Rational design of botulinum neurotoxin A1 mutants with improved oxidative stability
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
بیوشیمی، ژنتیک و زیست شناسی مولکولی (عمومی)
پیش نمایش صفحه اول مقاله
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چکیده انگلیسی
Botulinum neurotoxins (BoNTs) are the most potent toxic proteins to mankind known but applied in low doses trigger a localized muscle paralysis that is beneficial for the therapy of several neurological disorders and aesthetic treatment. The paralytic effect is generated by the enzymatic activity of the light chain (LC) that cleaves specifically one of the SNARE proteins responsible for neurotransmitter exocytosis. The activity of the LC in a BoNT-containing therapeutic can be compromised by denaturing agents present during manufacturing and/or in the cell. Stabilization of the LC by reducing vulnerability towards denaturants would thus be advantageous for the development of BoNT-based therapeutics. In this work, we focused on increasing the stability of LC of BoNT/A1 (LC/A1) towards oxidative stress. We tackled this task by rational design of mutations at cysteine and methionine LC/A1 sites. Designed mutants showed improved oxidative stability in vitro and equipotency to wildtype toxin in vivo. Our results suggest that suitable modification of the catalytic domain can lead to more stable BoNTs without impairing their therapeutic efficacy.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicon - Volume 147, 1 June 2018, Pages 54-57
Journal: Toxicon - Volume 147, 1 June 2018, Pages 54-57
نویسندگان
Manuela López de la Paz, Daniel Scheps, Marcel Jurk, Fred Hofmann, Jürgen Frevert,