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Cobra Cytotoxins: Structure, Evolution, Biological Activities, Underlying Molecular Mechanism, and...
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Cobra Cytotoxins: Structure, Evolution, Biological Activities, Underlying Molecular Mechanism, and Derived Bioactive Analogues

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Animal Venoms".

Deadline for manuscript submissions: closed (31 May 2024) | Viewed by 15685

Special Issue Editor

Dr. Peter V. Dubovskii

E-Mail Website
Guest Editor
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
Interests: cobra venom; proteomics; cytolytic peptides; antiproliferative activity; structure-functional relationship; antimicrobial peptide; template-based design of bioactive peptides; lipid/peptide interactions; apoptosis; action synergism

Special Issue Information

Dear Colleagues,  

Cobra cytotoxins (cardiotoxins) are representatives of the three-finger proteins, which constitute a substantial part of cobra and coral snake venom. They have a long history of investigation, with nearly half a century having elapsed since they were first isolated and the amino acid composition of the first representatives was determined. The views on the evolution and spatial structure of these molecules, their biological activity, and underlying mechanisms are scattered over this long period. This Special Issue is devoted to concentrating all these data and examining them with modern eyes, removing possible controversies. Moreover, newly emerging topics, including pharmacological applications of these molecules and derived analogues, are welcome.

Dr. Peter V. Dubovskii
Guest Editor

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Keywords

  • three-finger toxins
  • cobra cytotoxins
  • biological activity
  • mechanism of activity

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Published Papers (4 papers)

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Research

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13 pages, 3172 KiB  
Article
Membrane-Disrupting Activity of Cobra Cytotoxins Is Determined by Configuration of the N-Terminal Loop
by Peter V. Dubovskii, Anastasia A. Ignatova, Anna S. Alekseeva, Vladislav G. Starkov, Ivan A. Boldyrev, Alexey V. Feofanov and Yuri N. Utkin
Toxins 2023, 15(1), 6; https://doi.org/10.3390/toxins15010006 - 20 Dec 2022
Cited by 8 | Viewed by 2305
Abstract
In aqueous solutions, cobra cytotoxins (CTX), three-finger folded proteins, exhibit conformational equilibrium between conformers with either cis or trans peptide bonds in the N-terminal loop (loop-I). The equilibrium is shifted to the cis form in toxins with a pair of adjacent Pro residues [...] Read more.
In aqueous solutions, cobra cytotoxins (CTX), three-finger folded proteins, exhibit conformational equilibrium between conformers with either cis or trans peptide bonds in the N-terminal loop (loop-I). The equilibrium is shifted to the cis form in toxins with a pair of adjacent Pro residues in this loop. It is known that CTX with a single Pro residue in loop-I and a cis peptide bond do not interact with lipid membranes. Thus, if a cis peptide bond is present in loop-I, as in a Pro-Pro containing CTX, this should weaken its lipid interactions and likely cytotoxic activities. To test this, we have isolated seven CTX from Naja naja and N. haje cobra venoms. Antibacterial and cytotoxic activities of these CTX, as well as their capability to induce calcein leakage from phospholipid liposomes, were evaluated. We have found that CTX with a Pro-Pro peptide bond indeed exhibit attenuated membrane-perturbing activity in model membranes and lower cytotoxic/antibacterial activity compared to their counterparts with a single Pro residue in loop-I. Full article
(This article belongs to the Special Issue Cobra Cytotoxins: Structure, Evolution, Biological Activities, Underlying Molecular Mechanism, and Derived Bioactive Analogues)
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16 pages, 2670 KiB  
Article
Variability in the Spatial Structure of the Central Loop in Cobra Cytotoxins Revealed by X-ray Analysis and Molecular Modeling
by Peter V. Dubovskii, Kira M. Dubova, Gleb Bourenkov, Vladislav G. Starkov, Anastasia G. Konshina, Roman G. Efremov, Yuri N. Utkin and Valeriya R. Samygina
Toxins 2022, 14(2), 149; https://doi.org/10.3390/toxins14020149 - 18 Feb 2022
Cited by 11 | Viewed by 2693
Abstract
Cobra cytotoxins (CTs) belong to the three-fingered protein family and possess membrane activity. Here, we studied cytotoxin 13 from Naja naja cobra venom (CT13Nn). For the first time, a spatial model of CT13Nn with both “water” and “membrane” conformations of the central loop [...] Read more.
Cobra cytotoxins (CTs) belong to the three-fingered protein family and possess membrane activity. Here, we studied cytotoxin 13 from Naja naja cobra venom (CT13Nn). For the first time, a spatial model of CT13Nn with both “water” and “membrane” conformations of the central loop (loop-2) were determined by X-ray crystallography. The “water” conformation of the loop was frequently observed. It was similar to the structure of loop-2 of numerous CTs, determined by either NMR spectroscopy in aqueous solution, or the X-ray method. The “membrane” conformation is rare one and, to date has only been observed by NMR for a single cytotoxin 1 from N. oxiana (CT1No) in detergent micelle. Both CT13Nn and CT1No are S-type CTs. Membrane-binding of these CTs probably involves an additional step—the conformational transformation of the loop-2. To confirm this suggestion, we conducted molecular dynamics simulations of both CT1No and CT13Nn in the Highly Mimetic Membrane Model of palmitoiloleoylphosphatidylglycerol, starting with their “water” NMR models. We found that the both toxins transform their “water” conformation of loop-2 into the “membrane” one during the insertion process. This supports the hypothesis that the S-type CTs, unlike their P-type counterparts, require conformational adaptation of loop-2 during interaction with lipid membranes. Full article
(This article belongs to the Special Issue Cobra Cytotoxins: Structure, Evolution, Biological Activities, Underlying Molecular Mechanism, and Derived Bioactive Analogues)
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16 pages, 3048 KiB  
Article
Effects of Cardiotoxins from Naja oxiana Cobra Venom on Rat Heart Muscle and Aorta: A Comparative Study of Toxin-Induced Contraction Mechanisms
by Alexey S. Averin, Miroslav N. Nenov, Vladislav G. Starkov, Victor I. Tsetlin and Yuri N. Utkin
Toxins 2022, 14(2), 88; https://doi.org/10.3390/toxins14020088 - 24 Jan 2022
Cited by 16 | Viewed by 3985
Abstract
Cardiotoxins (CaTxs) are a group of snake toxins that affect the cardiovascular system (CVS). Two types (S and P) of CaTxs are known, but the exact differences in the effects of these types on CVS have not been thoroughly studied. We investigated cellular [...] Read more.
Cardiotoxins (CaTxs) are a group of snake toxins that affect the cardiovascular system (CVS). Two types (S and P) of CaTxs are known, but the exact differences in the effects of these types on CVS have not been thoroughly studied. We investigated cellular mechanisms of action on CVS for Naja oxiana cobra CaTxs CTX-1 (S-type) and CTX-2 (P-type) focusing on the papillary muscle (PM) contractility and contraction of aortic rings (AR) supplemented by pharmacological analysis. It was found that CTX-1 and CTX-2 exerted dose-dependent effects manifested in PM contracture and AR contraction. CTX-2 impaired functions of PM and AR more strongly than CTX-1. Effects of CaTxs on PM were significantly reduced by nifedipine, an L-type Ca2+ channel blocker, and by KB-R7943, an inhibitor of reverse-mode Na+/Ca2+ exchange. Furthermore, 2-aminoethoxydiphenyl borate, an inhibitor of store-operated calcium entry, partially restored PM contractility damaged by CaTxs. The CaTx influence on AR contracture was significantly reduced by nifedipine and KB-R7943. The involvement of reverse-mode Na+/Ca2+ exchange in the effect of CaTxs on the rat aorta was shown for the first time. The results obtained indicate that CaTx effects on CVS are mainly associated with disturbance of transporting systems responsible for the Ca2+ influx. Full article
(This article belongs to the Special Issue Cobra Cytotoxins: Structure, Evolution, Biological Activities, Underlying Molecular Mechanism, and Derived Bioactive Analogues)
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Review

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25 pages, 1668 KiB  
Review
Current Insights in the Mechanisms of Cobra Venom Cytotoxins and Their Complexes in Inducing Toxicity: Implications in Antivenom Therapy
by Bhargab Kalita, Yuri N. Utkin and Ashis K. Mukherjee
Toxins 2022, 14(12), 839; https://doi.org/10.3390/toxins14120839 - 1 Dec 2022
Cited by 15 | Viewed by 5296
Abstract
Cytotoxins (CTXs), an essential class of the non-enzymatic three-finger toxin family, are ubiquitously present in cobra venoms. These low-molecular-mass toxins, contributing to about 40 to 60% of the cobra venom proteome, play a significant role in cobra venom-induced toxicity, more prominently in dermonecrosis. [...] Read more.
Cytotoxins (CTXs), an essential class of the non-enzymatic three-finger toxin family, are ubiquitously present in cobra venoms. These low-molecular-mass toxins, contributing to about 40 to 60% of the cobra venom proteome, play a significant role in cobra venom-induced toxicity, more prominently in dermonecrosis. Structurally, CTXs contain the conserved three-finger hydrophobic loops; however, they also exhibit a certain degree of structural diversity that dictates their biological activities. In their mechanism, CTXs mediate toxicity by affecting cell membrane structures and membrane-bound proteins and activating apoptotic and necrotic cell death pathways. Notably, some CTXs are also responsible for depolarizing neurons and heart muscle membranes, thereby contributing to the cardiac failure frequently observed in cobra-envenomed victims. Consequently, they are also known as cardiotoxins (CdTx). Studies have shown that cobra venom CTXs form cognate complexes with other components that potentiate the toxic effects of the venom’s individual component. This review focuses on the pharmacological mechanism of cobra venom CTXs and their complexes, highlighting their significance in cobra venom-induced pathophysiology and toxicity. Furthermore, the potency of commercial antivenoms in reversing the adverse effects of cobra venom CTXs and their complexes in envenomed victims has also been discussed. Full article
(This article belongs to the Special Issue Cobra Cytotoxins: Structure, Evolution, Biological Activities, Underlying Molecular Mechanism, and Derived Bioactive Analogues)
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