المؤلفون: Lachlan D. Rash, Richard J. Lewis, Paul F. Alewood, Roberto Arreguín Espinosa, Ben Cristofori-Armstrong, Ai-Hua Jin, Sergio Agustín Román-González, Irina Vetter

المصدر: Biochemical Pharmacology. 164:342-348

مصطلحات موضوعية: 0301 basic medicine, Mollusk Venoms, Nicotinic Antagonists, Receptors, Nicotinic, Biochemistry, Cone snail, Xenopus laevis, 03 medical and health sciences, 0302 clinical medicine, Conus, Animals, Humans, Ion channel, Acid-sensing ion channel, Acetylcholine receptor, Pharmacology, Dose-Response Relationship, Drug, biology, Chemistry, Neuropeptides, Conus Snail, Biological activity, biology.organism_classification, Potassium channel, Acid Sensing Ion Channels, 030104 developmental biology, Nicotinic agonist, Acid Sensing Ion Channel Blockers, 030220 oncology & carcinogenesis, Female

الوصف: Conorfamides are a poorly studied family of cone snail venom peptides with broad biological activities, including inhibition of glutamate receptors, acid-sensing ion channels, and voltage-gated potassium channels. The aim of this study was to characterize the pharmacological activity of two novel linear conorfamides (conorfamide_As1a and conorfamide_As2a) and their non-amidated counterparts (conopeptide_As1b and conopeptide_As2b) that were isolated from the venom of the Mexican cone snail Conus austini. Although As1a, As2a, As1b and As2b were identified by activity-guided fractionation using a high-throughput fluorescence imaging plate reader (FLIPR) assay assessing α7 nAChR activity, sequence determination revealed activity associated with four linear peptides of the conorfamide rather than the anticipated α-conotoxin family. Pharmacological testing revealed that the amidated peptide variants altered desensitization of acid-sensing ion channels (ASICs) 1a and 3, and the native lysine to arginine mutation differentiating As1a and As1b from As2a and As2b introduced ASIC1a peak current potentiation. Surprisingly, these conorfamides also inhibited α7 and muscle-type nicotinic acetylcholine receptors (nAChR) at nanomolar concentrations. This is the first report of conorfamides with dual activity, with the nAChR activity being the most potent molecular target of any conorfamide discovered to date.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::78a4505422b3f42b22a6f5dee219d630Test
https://doi.org/10.1016/j.bcp.2019.04.025Test

المؤلفون: Qin Liu, Baldomero M. Olivera, Samuel D. Robinson, Joanna Gajewiak, Weishan Yang, Helena Safavi-Hemami, Samuel S. Espino

المصدر: Toxicon. 154:28-34

مصطلحات موضوعية: Male, 0301 basic medicine, Genetically modified mouse, Conus textile, Sensory Receptor Cells, Mollusk Venoms, Venom, Toxicology, Article, Conus spurius, Receptors, G-Protein-Coupled, Cone snail, Transcriptome, Mice, 03 medical and health sciences, Animals, Amino Acid Sequence, Conus victoriae, Receptor, Cells, Cultured, biology, Chemistry, Pruritus, Neuropeptides, biology.organism_classification, Cell biology, 030104 developmental biology, Conotoxins, Peptides

الوصف: Members of Mas related G-protein coupled receptors (Mrgpr) are known to mediate itch. To date, several compounds have been shown to activate these receptors, including chloroquine, a common antimalarial drug, and peptides of the RF-amide family. However, specific ligands for these receptors are still lacking and there is a need for novel compounds that can be used to modulate the receptors in order to understand the cellular and molecular mechanism in which they mediate itch. Some cone snail venoms were previously shown to induce itch in mice. Here, we show that the venom of Conus textile induces itch through activation of itch-sensing sensory neurons, marked by their sensitivity to chloroquine. Two RF-amide peptides, CNF-Tx1 and CNF-Tx2, were identified in a C. textile venom gland transcriptome. These belong to the conorfamide family of peptides which includes previously described peptides from the venoms of Conus victoriae (CNF-Vc1) and Conus spurius (CNF-Sr1 and CNF-Sr2). We show that CNF-Vc1 and CNF-Sr1 activate MrgprC11 whereas CNF-Vc1 and CNF-Tx2 activate the human MrgprX1 (hMrgprX1). The peptides CNF-Tx1 and CNF-Sr2 do not activate MrgprC11 or hMrgprX1. Intradermal injection of CNF-Vc1 and CNF-Tx2 into the cheek of a transgenic mouse expressing hMrgprX1 instead of endogenous mouse Mrgprs resulted in itch-related scratching thus demonstrating the in vivo activity of these peptides. Using truncated analogues of CNF-Vc1, we identified amino acids at positions 7 – 18 as important for activity against hMrgprX1. The conopeptides reported here are tools that can be used to advance our understanding of the cellular and molecular mechanism of itch mediated by Mrgprs.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::23b6eca16213a4e6233edfea875443f0Test
https://doi.org/10.1016/j.toxicon.2018.09.002Test

المؤلفون: Smriti, Moi, Shamasoddin, Shekh, Ashwini, Dolle, Marimuthu, Vijayasarathy, Konkallu Hanumae, Gowd

المصدر: Peptides. 156:170845

مصطلحات موضوعية: Propiophenones, Proline, Physiology, Conus Snail, Tryptophan, Mollusk Venoms, Peptides, Cyclic, Biochemistry, Molecular Docking Simulation, Oxidative Stress, Cellular and Molecular Neuroscience, Endocrinology, Animals, Trypsin, Disulfides, Peptides

الوصف: Distinct differences have been observed between L-tryptophan and D-tryptophan containing contryphan-Ar1131 in oxidative folding, trypsin binding, and photostabilization activity on avobenzone. [W

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0aba8a32e914cc3e4e3b2b45ea6881b3Test
https://doi.org/10.1016/j.peptides.2022.170845Test

المؤلفون: Ying Cao, Shang-Yi Liu, Ge Yao, Chong-Xu Fan, Xiandong Dai, Wenjian Wu, Penggang Han, Ji-Sheng Chen

المصدر: Toxicon. 135:17-23

مصطلحات موضوعية: 0301 basic medicine, Stereochemistry, Mollusk Venoms, Venom, Biology, Toxicology, Peptides, Cyclic, Chemical synthesis, Protein Structure, Secondary, Mice, 03 medical and health sciences, chemistry.chemical_compound, Conus, Animals, Contryphan, 030102 biochemistry & molecular biology, Conus betulinus, Conus Snail, biology.organism_classification, Pyrrolidonecarboxylic Acid, Transcriptome Sequencing, N-terminus, 030104 developmental biology, Biochemistry, chemistry, Pyroglutamic acid, Transcriptome

الوصف: A new member of the contryphans family was isolated from the venom of Conus betilinus, a vermivorous species distributed in the South China Sea. Its sequence, ZSGCO(D-W)KPWC-NH 2 (Z, pyroglutamic acid), was established by a combination of de novo MS/MS sequencing and venom-duct transcriptome sequencing. The occurrence of D-Trp 6 was confirmed by chemical synthesis and HPLC behavior comparison. Like known contryphans, contryphan-Bt produces the “stiff-tail” syndrome in mice and contains one disulfide bond, a hydroxyproline, a D-tryptophan, and an amidated C-terminus. However, contryphan-Bt differs from previously identified contryphans by a pyroglutamic acid at the N terminus. CD spectrum reveals that contryphan-Bt possess β-turn in solution.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ba706152d7b39e29aac31b685fadbda6Test
https://doi.org/10.1016/j.toxicon.2017.05.022Test

المؤلفون: Sanaz Dovell, Olga Chesnokov, Andrew V. Oleinikov, Frank Marí, Alberto Padilla, Mickelene Hoggard

المصدر: Journal of Proteomics

مصطلحات موضوعية: CD36 Antigens, 0301 basic medicine, Erythrocytes, Plasmodium falciparum, Protozoan Proteins, Biophysics, Mollusk Venoms, Poison control, Venom, Pharmacology, Biochemistry, Cone snail, 03 medical and health sciences, Protein Domains, Conus, Animals, Humans, Conotoxin, 030102 biochemistry & molecular biology, biology, SARS-CoV-2, Conus Snail, COVID-19, Intercellular Adhesion Molecule-1, biology.organism_classification, DNA Repair Enzymes, 030104 developmental biology, Conus nux, Transcription Factors

الوصف: Using high-throughput BioPlex assays, we determined that six fractions from the venom of Conus nux inhibit the adhesion of various recombinant PfEMP-1 protein domains (PF08_0106 CIDR1α3.1, PF11_0521 DBL2β3, and PFL0030c DBL3X and DBL5e) to their corresponding receptors (CD36, ICAM-1, and CSA, respectively). The protein domain-receptor interactions permit P. falciparum-infected erythrocytes (IE) to evade elimination in the spleen by adhering to the microvasculature in various organs including the placenta. The sequences for the main components of the fractions, determined by tandem mass spectrometry, yielded four T-superfamily conotoxins, one (CC-Loop-CC) with I-IV, II-III connectivity and three (CC-Loop-CXaaC) with a I-III, II-IV connectivity. The 3D structure for one of the latter, NuxVA = GCCPAPLTCHCVIY, revealed a novel scaffold defined by double turns forming a hairpin-like structure stabilized by the two disulfide bonds. Two other main fraction components were a miniM conotoxin, and a O2-superfamily conotoxin with cysteine framework VI/VII. This study is the first one of its kind suggesting the use of conotoxins for developing pharmacological tools for anti-adhesion adjunct therapy against malaria. Similarly, mitigation of emerging diseases like AIDS and COVID-19, can also benefit from conotoxins as inhibitors of protein-protein interactions as treatment. Biological significance Among the 850+ species of cone snail species there are hundreds of thousands of diverse venom exopeptides that have been selected throughout several million years of evolution to capture prey and deter predators. They do so by targeting several surface proteins present in target excitable cells. This immense biomolecular library of conopeptides can be explored for potential use as therapeutic leads against persistent and emerging diseases affecting non-excitable systems. We aim to expand the pharmacological reach of conotoxins/conopeptides by revealing their in vitro capacity to disrupt protein-protein and protein-polysaccharide interactions that directly contribute to pathology of Plasmodium falciparum malaria. This is significant for severe forms of malaria, which might be deadly even after treated with current parasite-killing drugs because of persistent cytoadhesion of P. falciparum infected erythrocytes even when parasites within red blood cells are dead. Anti-adhesion adjunct drugs would de-sequester or prevent additional sequestration of infected erythrocytes and may significantly improve survival of malaria patients. These results provide a lead for further investigations into conotoxins and other venom peptides as potential candidates for anti-adhesion or blockade-therapies. This study is the first of its kind and it suggests that conotoxins can be developed as pharmacological tools for anti-adhesion adjunct therapy against malaria. Similarly, mitigation of emerging diseases like AIDS and COVID-19, can also benefit from conotoxins as potential inhibitors of protein-protein interactions as treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::330d0991216d51c68d060cb0455a0544Test
https://doi.org/10.1016/j.jprot.2020.104083Test

المؤلفون: Helena Safavi-Hemami, Carolina Mӧller, Evan Clark, Anthony P. DeCaprio, Frank Marí

المصدر: Journal of Proteomics. 164:73-84

مصطلحات موضوعية: 0301 basic medicine, Biophysics, Hyaluronoglucosaminidase, Mollusk Venoms, Venom, Biochemistry, Conus purpurascens, Cone snail, 03 medical and health sciences, Protein Domains, Hyaluronidase, Conus, medicine, Animals, Amino Acid Sequence, Asparagine, Conotoxin, chemistry.chemical_classification, 030102 biochemistry & molecular biology, biology, Conus Snail, biology.organism_classification, Molecular biology, 030104 developmental biology, Enzyme, chemistry, medicine.drug

الوصف: Hyaluronidases are ubiquitous enzymes commonly found in venom and their main function is to degrade hyaluran, which is the major glycosaminoglycan of the extracellular matrix in animal tissues. Here we describe the purification and characterization of a 60 kDa hyaluronidase found in the injected venom from Conus purpurascens , Conohyal-P1. Using a combined strategy based on transcriptomic and proteomic analysis, we determined the Conohyal-P1 sequence. Conohyal-P1 has conserved consensus catalytic and positioning domain residues characteristic of hyaluronidases and a C-terminus EGF-like domain. Additionally, the enzyme is expressed as a mixture of glycosylated isoforms at five asparagine sites. The activity of the native Conohyal-P1 was assess MS-based methods and confirmed by classical turbidimetric methods. The MS-based assay is particularly sensitive and provides the first detailed analysis of a venom hyaluronidase activity monitored with this method. The discovery of new hyaluronidases and the development of techniques to evaluate their performance can advance several therapeutic procedures, as these enzymes are widely used for enhanced drug delivery applications. Biological significance Cone snail venom is a remarkable source of therapeutically important molecules, as is the case of conotoxins, which have undergone extensive clinical trials for several applications. In addition to the conotoxins, a large array of proteins have been reported in the venom of several species of cone snails, including enzymes that were found in dissected and injected Conus venom. Here we describe the isolation and characterization of the hyaluronidase Conohyal-P1 from the injected venom of C. purpurascens . We employed a combined transcriptomic and proteomic analysis to obtain the full sequence of this hyaluronidase. The activity of Conohyal-P1 was assessed by a mass spectrometry-based method, which provide the first detailed venom hyaluronidase activity analysis monitored by mass spectrometry allowing the visualization of the substrate degradation by the enzyme.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6ca0ec0b4e086858ee029100bef58260Test
https://doi.org/10.1016/j.jprot.2017.05.002Test

المؤلفون: Edwin De Pauw, Michel Degueldre, Nicolas Gilles, Marion Verdenaud, S. Zuñiga, Loïc Quinton, Garikoitz Legarda, Mathieu Leblanc, Rebeca Miñambres, Frédéric Ducancel

المصدر: Toxicon. 130:116-125

مصطلحات موضوعية: Proteomics, 0301 basic medicine, Mollusk Venoms, Toxicology, Bioinformatics, Cone snail, Transcriptome, 03 medical and health sciences, Tandem Mass Spectrometry, Conus, Animals, Protein Isoforms, Conotoxin, Conus Venoms, Phylogeny, biology, Sequence Analysis, RNA, Gene Expression Profiling, Conus Snail, Computational Biology, biology.organism_classification, 030104 developmental biology, Posttranslational modification, Protein Processing, Post-Translational, Chromatography, Liquid

الوصف: Venomous animals have developed a huge arsenal of reticulated peptides for defense and predation. Based on various scaffolds, they represent a colossal pharmacological diversity, making them top candidates for the development of innovative drugs. Instead of relying on the classical, low-throughput bioassay-guided approach to identify innovative bioactive peptides, this work exploits a recent paradigm to access to venom diversity. This strategy bypasses the classical approach by combining high-throughput transcriptomics, proteomics and bioinformatics cutting-edge technologies to generate reliable peptide sequences. The strategy employed to generate hundreds of reliable sequences from Conus venoms is deeply described. The study led to the discovery of (i) conotoxins that belong to known pharmacological families targeting various GPCRs or ion-gated channels, and (ii) new families of conotoxins, never described to date. It also focusses on the diversity of genes, sequences, folds, and PTM's provided by such species.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4e95baea6f94e72915a0d2f53e490e19Test
https://doi.org/10.1016/j.toxicon.2017.02.014Test

المؤلفون: Helena Safavi-Hemami, Samuel D. Robinson

المصدر: Toxicon. 123:56-61

مصطلحات موضوعية: 0301 basic medicine, medicine.medical_specialty, Modern medicine, medicine.medical_treatment, Prey capture, Mollusk Venoms, Toxicology, Insulin overdose, 03 medical and health sciences, Sequence Analysis, Protein, Internal medicine, Diabetes mellitus, Conus, Usually fatal, medicine, Animals, Insulin, Effective treatment, Intensive care medicine, Phylogeny, biology, Conus Snail, biology.organism_classification, medicine.disease, 030104 developmental biology, Endocrinology, Sequence Alignment

الوصف: The discovery of insulin and its use for the treatment of diabetes is undoubtedly one of the true successes of modern medicine. Injectable insulin would prove the first effective treatment for a previously incurable and usually fatal disease. Soon after however, the powerful effects of insulin overdose would be reported, and subsequently exploited for dubious medical and sometimes nefarious purposes. In this article we describe the discovery that certain venomous marine snails of the genus Conus also exploit the powerful effects of insulin overdose, employing it as a weapon for prey capture.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c9762e1bee844733fe15711a456e82e1Test
https://doi.org/10.1016/j.toxicon.2016.10.010Test

المؤلفون: Julita S. Imperial, Baldomero M. Olivera, Taleen Dilanyan, Manuel B. Aguilar, Pradip K. Bandyopadhyay, Samuel S. Espino, Russell W. Teichert

المصدر: Toxicon. 113:11-17

مصطلحات موضوعية: 0301 basic medicine, Glycine, Mollusk Venoms, Venom, Peptide, Toxicology, Bioinformatics, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Species Specificity, Dorsal root ganglion, Ganglia, Spinal, medicine, Animals, Amino Acid Sequence, Conotoxin, chemistry.chemical_classification, biology, Biological activity, biology.organism_classification, Molecular biology, Conus virgo, 030104 developmental biology, medicine.anatomical_structure, chemistry, Mollusca, Conotoxins, Sequence Alignment, 030217 neurology & neurosurgery, Conus terebra

الوصف: Cone snails in the Virgiconus clade prey on marine worms. Here, we identify six related conotoxins in the O1-superfamily from three species in this clade, Conus virgo, Conus terebra and Conus kintoki. One of these peptides, vi6a, was directly purified from the venom of C. virgo by following its activity using calcium imaging of dissociated mouse dorsal root ganglion (DRG) neurons. The purified peptide was biochemically characterized, synthesized and tested for activity in mice. Hyperactivity was observed upon both intraperitoneal and intracranial injection of the peptide. The effect of the synthetic peptide on DRG neurons was identical to that of the native peptide. Using the vi6a sequence, five other homologs were identified. These peptides define a glycine-rich subgroup of the O1-superfamily from the Virgiconus clade, with biological activity in mice.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::071d0988637e4b02d38e4b6e41b42fc6Test
https://doi.org/10.1016/j.toxicon.2016.02.001Test

المؤلفون: David J. Craik, J. Michael McIntosh, Peter N. Huynh, Peta J. Harvey, Joanna Gajewiak

المصدر: Biochem Pharmacol

مصطلحات موضوعية: 0301 basic medicine, Mollusk Venoms, Peptide, Nicotinic Antagonists, Receptors, Nicotinic, Biochemistry, Article, Xenopus laevis, 03 medical and health sciences, 0302 clinical medicine, Animals, Humans, Structure–activity relationship, Amino Acid Sequence, Conotoxin, Amino Acids, Ion channel, Acetylcholine receptor, Conus regius, Pharmacology, chemistry.chemical_classification, Binding Sites, Sequence Homology, Amino Acid, biology, Chemistry, biology.organism_classification, Rats, Protein Subunits, Nicotinic acetylcholine receptor, 030104 developmental biology, Nicotinic agonist, Amino Acid Substitution, 030220 oncology & carcinogenesis, Oocytes, Conotoxins

الوصف: The α9α10 nicotinic acetylcholine receptor (nAChR) has been characterized as an effective anti-pain target that functions through a non-opioid mechanism. However, as a pentameric ion channel comprised of two different subunits, the specific targeting of α9α10 nAChRs has proven challenging. Previously the 13-amino-acid peptide, RgIA, was shown to block α9α10 nAChRs with high potency and specificity. This peptide, characterized from the venom of the carnivorous marine snail, Conus regius, produced analgesia in several rodent models of chronic pain. Despite promising pre-clinical data in behavioral assays, the number of specific α9α10 nAChR antagonists remains small and the physiological mechanisms of analgesia remain cryptic. In this study, we implement amino-acid substitutions to definitively characterize the chemical properties of RgIA that contribute to its activity against α9α10 nAChRs. Using this mutational approach, we determined the vital role of biochemical side-chain properties and amino acids in the second loop that are amenable to substitutions to further engineer next-generation analogs for the blockade of α9α10 nAChRs.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cbb04f70f37ebcaf4db0024718bf0a65Test
https://doi.org/10.1016/j.bcp.2020.114124Test