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Present Status and Prospects for Use of Bacillus Thuringiensis H14 in Onchocerciasis Control
Published in Max J. Miller, E. J. Love, Parasitic Diseases: Treatment and Control, 2020
Selectivity — Extensive studies have been carried out in the laboratory (mammal safety tests) and in the field (environmental safety), which clearly proved the innocuity of B. thuringiensis H14. Recently it was shown that the endotoxin, which is in fact a protoxin, when hydrolized ( in vitro or in the gut of susceptible insects) is highly toxic for mammals upon injection but, fortunately, completely nontoxic upon ingestion.5 It is not known whether or not the fraction of the toxin (polypeptide) active against diptera upon ingestion and mammals upon injection is the same. However, this information has no practical significance for the use of B. thuringiensis H14 in vector control operations.
Diseases of the Nervous System
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Many biological toxins cause neurotoxicity. These include botulism, diphtheria and tetanus toxin, snake and bee venom, mushroom poisoning, and lathyrism.57,58,96,130,324,533,551,594 Botulism is associated with generalized weakness and bulbar dysfunction brought about bythe ingestion of spoiled food due to Clostridium botulinum contamination.533C. botulinum is a ubiquitous soil organism and its spores are very resistant. Botulinus toxin A is among the most lethal substances known, as little as 10-5 μg will kill a 20 g mouse. The toxin is synthesized under anaerobic conditions by C. botulinum.341 The protoxin is only slightly toxic; toxic residues are formed when proteolytic enzymes cleave certain amino acids from this molecule.171
The in vitro metabolism and in vivo pharmacokinetics of the bacterial β-glucuronidase inhibitor UNC10201652
Published in Xenobiotica, 2022
Anna Kerins, Marta Koszyczarek, Caroline Smith, Phil Butler, Rob Riley, Vamsi Madgula, Nilkanth Naik, Matthew R. Redinbo, Ian D. Wilson
Our understanding of the role of conjugates in the disposition and detoxication of drugs and xenobiotics has evolved significantly since these biotransformations were first described. Originally designated as a means to inactivate compounds and facilitate excretion, our more nuanced understanding of their effects includes the potential for bioactivation and toxicity. In particular, a number of the adverse drug reactions (ADRs) observed with carboxylic acid-containing non-steroidal anti-inflammatory drugs (NSAIDs) (Allison et al. 1992; Bjarnason et al. 1993) have been attributed to the chemical reactivity of their acyl glucuronides which, after excretion in the bile were at one time thought to directly damage the gut mucosa (e.g. see Boelsterli and Ramirez-Alcantara 2011). However, it now seems clear that this toxicity was in fact due to the release of the pharmacologically active aglycone, which can be blocked (at least in rodents) using novel, and specific gut commensal bacterial β-glucuronidase (GUS) inhibitors (LoGuidice et al. 2012; Saitta et al. 2014). Even where the glucuronides themselves are benign they can still act as a ‘prodrug’ (or actually a protoxin) that results in significant toxicity at a particular site. Thus, the dose-limiting gut toxicity of the anticancer drug irinotecan has been attributed to the hydrolysis of the glucuronide of its hydroxylated active metabolite (SN38), following excretion in the bile, by bacterial β-glucuronidases (Takasuna et al.1996). Studies in rodent models using specific bacterial β-glucuronidase inhibitors have also shown highly beneficial effects that can mitigate/eliminate gut toxicity by preventing the hydrolysis of both NSAID acyl glucuronides and the ether glucuronide of SN38 (e.g. Wallace et al. 2010; Bhatt et al. 2020).
Role of vacuolating cytotoxin A in Helicobacter pylori infection and its impact on gastric pathogenesis
Published in Expert Review of Anti-infective Therapy, 2020
Shamshul Ansari, Yoshio Yamaoka
H. pylori VacA is a pore-forming cytotoxin that interacts with gastric epithelial cells and plays a crucial role in pathogenicity [9,10]. After its initial formation as a 140 kDa protoxin, VacA is secreted through the autotransporter system. The mature VacA that is secreted from H. pylori consists of an 88 kDa monomer that undergoes limited proteolysis to yield two fragments; an N-terminal p33 domain (amino acids 1 to 311) and a C-terminal p55 domain (amino acids 312 to 821), which are linked by a flexible loop that is sensitive to limited proteolysis in vitro (Figure 1(a)) [11,12]. Moreover, ∼15 Å resolution cryo-electron microscopy (cryo-EM) has been used to elucidate the structure of various VacA oligomers and reveals the interactions between the p33 and p55 domains for VacA assembly [13]. The p55 domain performs host cell receptor binding activity, whereas the p33 domain is responsible for pore-forming activity [14]. The 2.4 Å crystal structure of the p55 domain reveals a predominant right-handed β-helix [15]. Furthermore, the 19 Å cryo-EM structure of the VacA dodecamer reveals the p55 domain as the peripheral arms of the flower-like structure and the p33 domain as the central core [16]. Further investigation has shown that the binding interface of p33-p55 is approximately 1,300 Å2 and involves two salt bridges (H276-D360 and E295-K353) at the loops of the β-helix, as well as three side-chain hydrogen bonds (H276-D360, D281-N363, and E295-K353) [17]. Moreover, the laterally connected β-strands are stabilized by the main chains of the two domains (residues 275–293 and residues 352–380), which are close enough to form multiple main-chain hydrogen bonds [18]. Multiple tryptophan residues (W49, W80, W82, W90, and W96) in the p33 domain play an important role in the membrane-binding process [192021–22]. However, the entire p33 domain and 111 N-terminal amino acid residues in the p55 domain are required to achieve efficient vacuolating capability [23].
Advances in venom peptide drug discovery: where are we at and where are we heading?
Published in Expert Opinion on Drug Discovery, 2021
Taylor B. Smallwood, Richard J. Clark
With recent improvements in research techniques and processes, and a renewed focus for venom-derived drugs, the number of candidates in the development pipeline is increasing exponentially [2]. Current analytical technology now allows for the identification of venom peptides from species that provide only miniscule amounts of venom. Spiders, which produce less than 10 µL of venom, are considered the most successful terrestrial predators [2]. From the 42,000 species described to date [82], it is believed that their venom is likely to contain at least 10 million bioactive peptides [2]. Spider venom is abundant with disulfide-rich peptides, with inhibitory cysteine knot (ICK) peptides dominating most spider venom peptidomes [83]. This family of peptides possesses a unique structural motif consisting of a triplet-stranded antiparallel β-sheet stabilized by three disulfide bridges [84]. A knot is formed when two of the disulfide bonds create a ring that is penetrated by the third disulfide bond. The knotted topology creates a very stable structure that is resistant to heat denaturation and proteolysis [85]. Some ICK peptides exhibit unique pharmacological properties by modulating key membrane proteins such as the voltage-gated sodium channels (Nav1.1–1.9) [86]. The Nav channels are essential to the initiation and propagation of action potentials in excited cells and are thought to play a key role in the pathogenesis of many neurological disorders including chronic pain and epilepsy. Several species of tarantulas possess venom containing ICK peptides, which show potential to treat a range of neurological disorders. Protoxin-II [87], Huwentoxin IV [88], µ-theraphotoxin-Pn3a [89], Ceratotoxin-1 [90], and GpTx-1 [91] are ICK peptides currently in preclinical development as potential future analgesics. Other tarantula toxins like 40-residue Psalmotoxin 1 (PcTx1) [92] and the 76-residue Hi1A toxin [93] from the Australian funnel web (Hadronyche infensa) are reported to potently inhibit the ASIC1a ion channel. ASIC1a is a primary acid sensor in mammalian brain that is considered as a key mediator of stroke-induced neuronal damage [93]. Compared to PcTx1, Hi1a is a slightly more selective and potent inhibitor of ASIC1a, and is a potential lead for the development as a neuroprotective agent as it strongly attenuates brain damage after a stroke [93,94].