The First Recombinant Viper Three-Finger Toxins: Inhibition of Muscle and Neuronal Nicotinic Acetylcholine Receptors

Makarova, Ya. V.; Kryukova, Elena V.; Shelukhina, Irina V.; Lebedev, Dmitry; Андреева, Т. В.; Ryazantsev, D. Yu.; Balandin, Sergey V.; Ovchinnikova, Tatiana V.; Tsetlin, Victor I.; Utkin, Yuri N.

doi:10.1134/s1607672918020205

Cited by 15 publications

(10 citation statements)

References 14 publications

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“…Five three-finger toxins were found in A. feae venom ( Figure 5 ); according to their amino acid sequences, they represent so-called basal (commonly known as non-conventional) toxins containing the fifth disulfide bond in the first loop [ 29 , 30 ]. The recombinant toxin 3FTx-Aze-2 showed the capacity to interact with muscle type and neuronal nicotinic acetylcholine receptors [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

“…The first step to investigate the biological activity of A. feae three-finger toxins is our recent work, where the gene encoding the sequence of 3FTx-Aze-2 ( Figure 5) was synthesized, expressed in Escherichia. coli, and the biological activity studies showed that the heterologously expressed toxin inhibited nicotinic acetylcholine receptors of both muscle and neuronal types [31].…”

Section: Discussionmentioning

confidence: 99%

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Novel Bradykinin-Potentiating Peptides and Three-Finger Toxins from Viper Venom: Combined NGS Venom Gland Transcriptomics and Quantitative Venom Proteomics of the Azemiops feae Viper

et al. 2020

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Feae’s viper Azemipos feae belongs to the Azemiopinae subfamily of the Viperidae family. The effects of Viperidae venoms are mostly coagulopathic with limited neurotoxicity manifested by phospholipases A2. From A. feae venom, we have earlier isolated azemiopsin, a novel neurotoxin inhibiting the nicotinic acetylcholine receptor. To characterize other A. feae toxins, we applied label-free quantitative proteomics, which revealed 120 unique proteins, the most abundant being serine proteinases and phospholipases A2. In total, toxins representing 14 families were identified, among which bradykinin-potentiating peptides with unique amino acid sequences possessed biological activity in vivo. The proteomic analysis revealed also basal (commonly known as non-conventional) three-finger toxins belonging to the group of those possessing neurotoxic activity. This is the first indication of the presence of three-finger neurotoxins in viper venom. In parallel, the transcriptomic analysis of venom gland performed by Illumina next-generation sequencing further revealed 206 putative venom transcripts. Together, the study unveiled the venom proteome and venom gland transciptome of A. feae, which in general resemble those of other snakes from the Viperidae family. However, new toxins not found earlier in viper venom and including three-finger toxins and unusual bradykinin-potentiating peptides were discovered.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Novel Bradykinin-Potentiating Peptides and Three-Finger Toxins from Viper Venom: Combined NGS Venom Gland Transcriptomics and Quantitative Venom Proteomics of the Azemiops feae Viper

et al. 2020

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“…To address the question of biological activity of Viperidae TFTs, two toxins were obtained by heterologous expression in Escherichia coli . Based on the nucleotide sequences of cDNA encoding TFTs in the venom glands of vipers Azemiops feae and Vipera nikolskii , the corresponding genes optimized for bacterial expression were synthesized[20]. Expressed A. feae TFT (TFT-AF) and V. nikolskii TFT (VN-TFT), both of the nonconventional type, were refolded under the conditions elaborated on earlier for cobra TFTs.…”

Section: Recentlty-discovered Tfts With New Structural Featuresmentioning

confidence: 99%

“…Both toxins inhibited neuronal α3-containing and muscle-type nAChRs in the micromolar concentration range, but they were each very weak antagonists of neuronal α7 nAChRs. Thus, viper TFTs can function as antagonists of nAChRs of neuronal and muscle-type[20].…”

Section: Recentlty-discovered Tfts With New Structural Featuresmentioning

confidence: 99%

Last decade update for three-finger toxins: Newly emerging structures and biological activities

Utkin

2019

WJBC

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Three-finger toxins (TFTs) comprise one of largest families of snake venom toxins. While they are principal to and the most toxic components of the venoms of the Elapidae snake family, their presence has also been detected in the venoms of snakes from other families. The first TFT, α-bungarotoxin, was discovered almost 50 years ago and has since been used widely as a specific marker of the α7 and muscle-type nicotinic acetylcholine receptors. To date, the number of TFT amino acid sequences deposited in the UniProt Knowledgebase free-access database is more than 700, and new members are being added constantly. Although structural variations among the TFTs are not numerous, several new structures have been discovered recently; these include the disulfide-bound dimers of TFTs and toxins with nonstandard pairing of disulfide bonds. New types of biological activities have also been demonstrated for the well-known TFTs, and research on this topic has become a hot topic of TFT studies. The classic TFTs α-bungarotoxin and α-cobratoxin, for example, have now been shown to inhibit ionotropic receptors of γ-aminobutyric acid, and some muscarinic toxins have been shown to interact with adrenoceptors. New, unexpected activities have been demonstrated for some TFTs as well, such as toxin interaction with interleukin or insulin receptors and even TFT-activated motility of sperm. This minireview provides a summarization of the data that has emerged in the last decade on the TFTs and their activities.

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“…In addition, this information can find its way into diagnostics 97,98 and allow for more efficient ways of the recombinant expression of snake venom toxins, such as recombinant viper three-finger toxins studied as potent inhibitors of nAChRs. 99 Furthermore, other applications for these compounds are found, such as in cosmetics 100,101 and pesticides. 102–104…”

Section: Sourcesmentioning

confidence: 99%

Drug Discovery on Natural Products: From Ion Channels to nAChRs, from Nature to Libraries, from Analytics to Assays

et al. 2019

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Natural extracts are complex mixtures that may be rich in useful bioactive compounds and therefore are attractive sources for new leads in drug discovery. This review describes drug discovery from natural products and in explaining this process puts the focus on ion-channel drug discovery. In particular, the identification of bioactives from natural products targeting nicotinic acetylcholine receptors (nAChRs) and serotonin type 3 receptors (5-HT3Rs) is discussed. The review is divided into three parts: “Targets,” “Sources,” and “Approaches.” The “Targets” part will discuss the importance of ion-channel drug targets in general, and the α7-nAChR and 5-HT3Rs in particular. The “Sources” part will discuss the relevance for drug discovery of finding bioactive compounds from various natural sources such as venoms and plant extracts. The “Approaches” part will give an overview of classical and new analytical approaches that are used for the identification of new bioactive compounds with the focus on targeting ion channels. In addition, a selected overview is given of traditional venom-based drug discovery approaches and of diverse hyphenated analytical systems used for screening complex bioactive mixtures including venoms.

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The First Recombinant Viper Three-Finger Toxins: Inhibition of Muscle and Neuronal Nicotinic Acetylcholine Receptors

Cited by 15 publications

References 14 publications

Novel Bradykinin-Potentiating Peptides and Three-Finger Toxins from Viper Venom: Combined NGS Venom Gland Transcriptomics and Quantitative Venom Proteomics of the Azemiops feae Viper

Novel Bradykinin-Potentiating Peptides and Three-Finger Toxins from Viper Venom: Combined NGS Venom Gland Transcriptomics and Quantitative Venom Proteomics of the Azemiops feae Viper

Last decade update for three-finger toxins: Newly emerging structures and biological activities

Drug Discovery on Natural Products: From Ion Channels to nAChRs, from Nature to Libraries, from Analytics to Assays

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