Abstract
Botulinum neurotoxin serotype A (BoNTA) is widely used for treating neuromuscular disorders. Despite of the various marketed products, BoNTA is known to have small therapeutic index ranging from 5 to 15. In the present study, we designed and characterized engineered BoNTA proteins with fusion of cell-penetrating peptides (CPPs). We have shown that CPPs, particularly a recently reported zinc finger protein could improve the cellular uptake and intramuscular therapeutic index of BoNTA. Our study has shed the light on developing next-generation neuromuscular modulators using CPP fusion.
Highlights
Botulinum neurotoxins (BoNTs) are neurotoxic proteins produced by Clostridium botulinum and related bacterial species (Rossetto et al, 2014)
We found that cell-penetrating peptides (CPPs) fusion affected the cleavage activity of Botulinum neurotoxin serotype A (BoNTA) by different manners and degrees (Figure 1C)
Native BoNTA contains heavy chain (HC) and light chain (LC) domains that are responsible for cellular translocation and target cleavage (Rossetto et al, 2014)
Summary
Botulinum neurotoxins (BoNTs) are neurotoxic proteins produced by Clostridium botulinum and related bacterial species (Rossetto et al, 2014). BoNTA-containing protein complexes ona-, aboand incobotulinum have been developed as commercial products under the trade names of Botox, Dysport, and Xeomin, respectively These products are widely used as therapeutic and cosmetic agents and have been approved for treating a wide range of neuromuscular disorders. While the overall patient satisfaction of injectable BoNTA is above 80%, an increasing number of severe and long-term adverse effects have been observed with the constantly expanding medical indications (Lim and Seet, 2010) These adverse effects are largely due to the suboptimal diffusion of BoNTA and its narrow therapeutic index of 5–15 (Aoki, 2001; Comella et al, 2005; Rossetto et al, 2014). In order to overcome the limitations on small therapeutic index and drug safety, engineering endeavors are needed to improve the pharmacological properties of BoNTA proteins
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