A rare case of Panophthalmitis due to cobra bite

Purpose Ocular manifestations of snake bite are rare, ranging from direct injury to the eye from snake venom or indirect injury due to antivenom. We report a rare case of cobra bite causing panophthalmitis due to indirect injury as a result of snake venom toxin related tissue necrosis and susceptibility to secondary infections. Methods Observational case report. External photographs, slit lamp photos, ultrasonography of the eye and histopathology of the eviscerated eye were used to characterize and describe the clinical findings. Thirty-nine-years-old male farmer presented with history of cobra snake bite on his right index finger and developed right eye sudden onset pain and redness 3 days later. On examination, features were suggestive of panophthalmitis and the eye had to be eviscerated with scleral excision. Conclusion It is important for ophthalmologist to be aware of such grave consequences of snake bite to be prepared for the emergency management of such cases.

Structure and selectivity engineering of the M1 muscarinic receptor toxin complex

Muscarinic toxins (MTs) are natural toxins produced by mamba snakes that primarily bind to muscarinic acetylcholine receptors (MAChRs) and modulate their function. Despite their similar primary and tertiary structures, MTs show distinct binding selectivity toward different MAChRs. The molecular details of how MTs distinguish MAChRs are not well understood. Here, we present the crystal structure of M1AChR in complex with MT7, a subtype-selective anti-M1AChR snake venom toxin. The structure reveals the molecular basis of the extreme subtype specificity of MT7 for M1AChR and the mechanism by which it regulates receptor function. Through in vitro engineering of MT7 finger regions that was guided by the structure, we have converted the selectivity from M1AChR toward M2AChR, suggesting that the three-finger fold is a promising scaffold for developing G protein–coupled receptor modulators.

Molecular Modelling and Docking Experiments Examining the Interaction between SARS-CoV-2 Spike Glycoprotein and Neuronal Nicotinic Acetylcholine Receptors

While SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) as the receptor for cell entry, it is important to examine for other potential interactions between the virus and other cell receptors. Based on the clinical observation of low smoking prevalence among hospitalized COVID-19 patients, we recently identified a “toxin-like” amino acid (aa) sequence on the receptor binding domain of the spike glycoprotein of SARS-CoV-2 (aa 375-390) with homology to a sequence of a snake venom toxin, which could interact with nicotinic acetylcholine receptors (nAChRs). We now present computational molecular modelling and docking experiments using 3D structures of the SARS-CoV-2 spike glycoprotein and the extracellular domain of the nAChR alpha9 subunit. We identified an interaction between the aa381-386 of the SARS-CoV-2 spike glycoprotein and the aa189-192 of the extracellular domain of the nAChR alpha9 subunit, a region which forms the core of the “toxin-binding site” of the nAChRs. The mode of interaction is very similar to the interaction between the alpha9 nAChR and alpha-bungarotoxin. A similar interaction was observed between the pentameric alpha7 AChR and the SARS-CoV-2 spike glycoprotein. Our findings support the hypothesis that severe COVID-19 may be associated with disruption of the nicotinic cholinergic system which could be caused by an interaction between SARS-CoV-2 and nAChRs.

Nicotinic Cholinergic System and COVID-19: Identification of a Potentially Crucial Snake Toxin-Like Sequence in the SARS-CoV-2 Spike Glycoprotein

Smoking is a risk factor for respiratory infections and there is reasonable concern that it may affect COVID-19 susceptibility and severity. Recent studies have focused on the interaction between smoking (and nicotine) and ACE2 expression, suggesting that ACE2 up-regulation could contribute to enhanced viral cell entry. However, case series have shown that there is an unexpectedly low prevalence of smoking among hospitalized COVID-19 cases. Since early April, we were the first to hypothesize that dysfunction of the nicotinic cholinergic system (NCS) may be implicated in the pathophysiology of severe COVID-19. We recently reported that many of the clinical manifestations of severe COVID-19 could be explained by dysregulation of the NCS. In this study, we present an amino acid sequence in the receptor binding domain of the SARS-CoV-2 Spike glycoprotein which is homologous to a sequence of a snake venom toxin. We present the 3D structural location of this “toxin-like” sequence on the Spike Glycoprotein. These findings suggest that SARS-CoV-2 could potentially interact with acetylcholine receptors causing dysregulation of the NCS and the cholinergic anti-inflammatory pathway.

Structural basis for phospholipase A2-like toxin inhibition by the synthetic compound Varespladib (LY315920)

The World Health Organization recently listed snakebite envenoming as a Neglected Tropical Disease, proposing strategies to significantly reduce the global burden of this complex pathology by 2030. In this context, effective adjuvant treatments to complement conventional antivenom therapy based on inhibitory molecules for specific venom toxins have gained renewed interest. Varespladib (LY315920) is a synthetic molecule clinically tested to block inflammatory cascades of several diseases associated with elevated levels of secreted phospholipase A2 (sPLA2). Most recently, Varespladib was tested against several whole snake venoms and isolated PLA2 toxins, demonstrating potent inhibitory activity. Herein, we describe the first structural and functional study of the complex between Varespladib and a PLA2-like snake venom toxin (MjTX-II). In vitro and in vivo experiments showed this compound’s capacity to inhibit the cytotoxic and myotoxic effects of MjTX-II from the medically important South American snake, Bothrops moojeni. Crystallographic and bioinformatics analyses revealed interactions of Varespladib with two specific regions of the toxin, suggesting inhibition occurs by physical blockage of its allosteric activation, preventing the alignment of its functional sites and, consequently, impairing its ability to disrupt membranes. Furthermore, based on the analysis of several crystallographic structures, a distinction between toxin activators and inhibitors is proposed.

SVDB: a Comprehensive Domain Specific Database of Snake Venom Toxins Generated Through NCBI

Venoms that drip from the fangs of snakes are incredibly complex chemical cocktails of compounds, with different proteins and enzymes, including a large variety of toxins like myotoxins, cardiotoxins, hemotoxins, and neurotoxins and their countless combinations. In addition to their use in the treatment of snake bites in humans, they have numerous therapeutic and medicinal applications. Potential use of snake venom includes excessive bleeding, stroke, neurological disorders, cancer, diabetes and aging. Therefore, a proper understanding of snake venom toxin and facilitating their use is of utmost importance. In this paper, we describe a novel database, called SVDB, for storage, dissemination and analysis of snake venom and toxins related information. SVDB has autonomous links to NCBI databases to pull relevant information both on-demand and asynchronous ways to facilitate data integration. SVDB includes authentic, non-redundant, up-to-date scientific information on literature, sequences, structures, small molecules, taxonomy and many more. SVDB portal also provides external links to tools like BLAST, CLUSTAL, Swiss-model, phylogeny and other toxin related resources. The architecture of SVDB information fetching, linking and structuring is unique and can be implemented to any domain specific generic data collection pipeline through the NCBI. The database is publicly available at https://www.snakevenomdb.org.