Botulinum neurotoxins (BoNTs) can cause nerve paralysis syndrome in mammals and other vertebrates. BoNTs are the most toxic biotoxins known and are classified as Class A biological warfare agents. BoNTs are mainly divided into seven serotypes A-G and new neurotoxins BoNT/H and BoNT/X, which have similar functions. BoNT proteins are 150 kDa polypeptide consisting of two chains and three domains: the light chain (L, catalytic domain, 50 kDa) and the heavy chain (H, 100 kDa), which can be divided into an N-terminal membrane translocation domain (HN, 50 kDa) and a C-terminal receptor binding domain (Hc, 50 kDa). In current study, we explored the immunoprotective efficacy of each functional molecule of BoNT/F and the biological characteristics of the light chain-heavy N-terminal domain (FL-HN). The two structure forms of FL-HN (i.e., FL-HN-SC: single chain FL-HN and FL-HN-DC: di-chain FL-HN) were developed and identified. FL-HN-SC could cleave the vesicle associated membrane protein 2 (VAMP2) substrate protein in vitro as FL-HN-DC or FL. While only FL-HN-DC had neurotoxicity and could enter neuro-2a cells to cleave VAMP2. Our results showed that the FL-HN-SC had a better immune protection effect than the Hc of BoNT/F (FHc), which indicated that L-HN-SC, as an antigen, provided the strongest protective effects against BoNT/F among all the tested functional molecules. Further in-depth research on the different molecular forms of FL-HN suggested that there were some important antibody epitopes at the L-HN junction of BoNT/F. Thus, FL-HN-SC could be used as a subunit vaccine to replace the FHc subunit vaccine and/or toxoid vaccine, and to develop antibody immune molecules targeting L and HN domains rather than the FHc domain. FL-HN-DC could be used as a new functional molecule to evaluate and explore the structure and activity of toxin molecules. Further exploration of the biological activity and molecular mechanism of the functional FL-HN or BoNT/F is warranted.

https://www.mdpi.com/2072-6651/15/3/200/pdf?version=1678085200

Biological and Immunological Characterization of a Functional L-HN Derivative of Botulinum Neurotoxin Serotype F

Despite the expanding clinical utility of botulinum neurotoxins, there remain problems to be solved for attaining the best outcome. The efficacy and safety need to be reconsidered for commercially available preparations all derived from subtype A1 or B1. Emerging new toxins include A2 or A6 subtypes or engineered toxins with less spread, more potency, longer durations of action, less antigenicity and better safety profile than currently used preparations. Non-toxic BoNTs with a few amino acid replacements of the light chain (LC) may have a role as a drug-delivery system if the toxicity is abolished entirely. At present, efficacy of these BoNTs in animal botulism was demonstrated. 

A look at the future-new BoNTs and delivery systems in development: What it could mean in the clinic.

Currently, eight natural serotypes of botulinum neurotoxin (BNT-A-G, -X) are known. The mechanism of action of all BNT serotypes is presynaptic blockade of SNARE transport proteins (Soluble N-ethylmaleimide-sensitive factor [NSF] Attachment Protein Receptor), as a result of which the release of acetylcholine into the synaptic cleft is disrupted and neuromuscular transmission is blocked. Each botulinum toxin serotype selectively binds to its own presynaptic membrane receptor and causes cleavage of its own SNARE protein. These differences determine the neuronal specificity and activity of botulinum toxins, which leads to their unique pharmacological properties, such as activity, duration of action, and time to onset of action. In the international clinical practice, only two BNT serotypes (A and B) are allowed to be used, however, in recent years, a large number of studies on the efficacy and safety of other BNT serotypes (E, C, F) have been carried out, and technologies for changing their natural properties have been developed. One of the indications for the use of botulinum therapy in neurology is the correction of post-stroke spasticity. Currently, BNT-A is used for this purpose, clinical improvement after its injection occurs after 2 weeks, the therapeutic effect persists for 3 months, and then the symptoms of spasticity increase again, which worsens the patient's quality of life and reduces the possibility of medical rehabilitation. The use of fast-acting recombinant botulinum toxins for this purpose could help overcome this disadvantage of BNT-A therapy. Currently the LANTIMA study, supported by IPSEN company, is going on to evaluate the safety profile and level of efficacy of modified recombinant botulinum toxin type AB in the treatment of upper limb spasticity in adults. 

Recombinant botulinum toxin as a new stage in the development of botulinum toxin therapy. Possibilities and perspectives of use in neurological practice

Botulinum toxin type A (BTX-A), produced by the gram-positive anaerobic bacterium Clostridium botulinum, acts by cleaving synaptosome-associated protein-25 (SNAP-25), an essential component of the presynaptic neuronal membrane that is necessary for fusion with the membrane proteins of neurotransmitter-containing vesicles. Recent studies have highlighted the efficacy of BTX-A in treating chronic pain conditions, including lower back pain, chronic neck pain, neuropathic pain, and trigeminal neuralgia, particularly when patients are unresponsive to traditional painkillers. This review focuses on the analgesic effects of BTX-A in various chronic pain conditions, with a particular emphasis on the orofacial region. 

Botulinum toxin type A is a potential therapeutic drug for chronic orofacial pain

Neutralizing chimeric heavy-chain antibody targeting the L-HN domain of Clostridium botulinum neurotoxin type F

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.

New Modified Recombinant Botulinum Neurotoxin Type F with Enhanced Potency

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New Modified Recombinant Botulinum Neurotoxin Type F with Enhanced Potency