conopeptide (U2902) / TuHURA Bio - LARVOL DELTA

A fluorescent screening method for optimization of conotoxin expression in Pichia pastoris. (PubMed, Biotechnol Appl Biochem) - "Here, we explore the Pichia pastoris to express 23 selected conopeptides using a GFP-based fluorescence screen...Furthermore, the recombinant ?TxIA after cleavage from the fusion was able to inhibit cell proliferation of the LYCT and HEK293T cell lines with an appearance IC of 341 ± 8 and 235 ± 15 nM, respectively. This screening method is straightforward and easy to scale-up, providing a versatile tool for further optimization of conotoxin production in the yeast cell."

Journal • PAICS

A novel proline-rich M-superfamily conotoxin that can simultaneously affect sodium, potassium and calcium currents. (PubMed, J Venom Anim Toxins Incl Trop Dis) - "Vr3a can simultaneously affect sodium, potassium and calcium currents. This novel triple-target conotoxin Vr3a expands understanding of conotoxin functions."

Journal

[VIRTUAL] Analgesic effect of a novel ?-conotoxin after systemic administration. (IASP 2021) - "These toxins are isolated from the venom of marine snails, belonging to the genus Conus. Ziconotide (known commercially as Prialt®, a Primary alternative to morphine) is a peptide derived from the marine snail, Conus magus, is a potent analgesic for the treatment of chronic refractory pain. The challenge of Ziconotide is that has to be administered by intrathecal infusions and this creates a problem for the patient and the health system To our knowledge, this is the first omega-conotoxin with analgesic activity by systemic administration and could be the first conopeptide that can be administered without catheter implantation, improving the economy and quality of life of patients. Furthermore, no side effects as opioids are produced."

Addiction (Opioid and Alcohol) • Pain

[VIRTUAL] Alleviation of chronic SCI pain in rats by recombinant GABAergic cells releasing conopeptide MVIIA (IASP 2021) - "The omega-conopeptide, MVIIA, an N-type Ca2+ channel blocker, was one of the earliest tested treatments for severe pain in animal models and is in clinical use marketed as FDA approved Prialt (Ziconotide)...Conditioned place preference with gabapentin revealed significant reduction of ongoing pain in animals with the grafts... Our results demonstrate the beneficial and targeted effect and potency of recombinant cell-based therapy in the management of chronic pain."

Preclinical • CNS Disorders • Complement-mediated Rare Disorders • Immunology • Neuralgia • Orthopedics • Pain • Peripheral Neuropathic Pain • Transplantation

Hormone-like conopeptides - new tools for pharmaceutical design. (PubMed, RSC Med Chem) - "Finally, we briefly examine methods of chemically stabilizing conopeptides to improve their pharmacological properties. A summary is presented of conopeptides in clinical trials and a call for future work on hormone-like conopeptides."

Journal • Review

Non-Peptidic Small Molecule Components from Cone Snail Venoms. (PubMed, Front Pharmacol) - "These venom components ("conotoxins, conopeptides") have been widely studied in many laboratories, leading to pharmaceutical agents and probes...The compounds so far characterized are active on neurons and thus may potentially serve as leads for neuronal diseases. Thus, in analogy to the incredible pharmacopeia resulting from studying venom peptides, these small molecules may provide a new resource of pharmacological agents."

Journal • Review

Proteogenomic Assessment of Intraspecific Venom Variability: Molecular Adaptations in the Venom Arsenal of Conus purpurascens. (PubMed, Mol Cell Proteomics) - "Cone snails produce venom that contains diverse groups of peptides (conopeptides/conotoxins) and display a wide mass range, high rate of post-translational modifications, and many potential pharmacological targets...The results reveal two distinct venom profiles with different synergistic interactions to effectively target neural pathways aimed to immobilize prey. These venom expression patterns will aid target prediction, a significant step towards developing conotoxins into valuable drugs or neural probes."

Journal

Diversity of Conopeptides and Conoenzymes from the Venom Duct of the Marine Cone Snail Conus bayani as Determined from Transcriptomic and Proteomic Analyses. (PubMed, Mar Drugs) - "Importantly, herein we document the presence of 16 proteins that include five post-translational modifying enzymes obtained from transcriptomic data. Our results revealed diverse and novel conopeptides of an unexplored species that could be used extensively in biomedical research due to their therapeutic potentials."

Journal

The Redox-Active Conopeptide Derived from the Venom Duct Transcriptome of Conus lividus Assists in the Oxidative Folding of Conotoxin. (PubMed, Biochemistry) - "Hydrogen bonding of the hydroxyl group of 4-trans-hydroxyproline with the interpeptide chain unit in the mixed disulfide form may play a vital role in shifting the geometry of the Cys1-Hyp2 peptide bond from cis to trans configuration. The Li520 conopeptide together with similar peptides derived from other species may constitute a new family of "redox-active" conopeptides that are integral components of the oxidative folding machinery of conotoxins."

Journal • GLRX

Cannabinoid receptor agonists from Conus venoms alleviate pain-related behavior in rats. (PubMed, Pharmacol Biochem Behav) - "Further HPLC purification revealed two potent antinociceptive subfractions within C. Tex with CB1 and possible CB2 activity, with mild to no side effects in the CB tetrad assessment. CB conopeptides can be isolated from these active Conus venom-derived samples and further developed as novel analgesic agents for the treatment of chronic pain using cell based or gene therapy approaches."

Journal • Preclinical • Gene Therapies • Pain

Acute toxicity and micronucleus test of conotoxin lt14a in mice. (PubMed, Basic Clin Pharmacol Toxicol) - "The high dose of lt14a (1000 times the effective analgesic dose) had a certain damaging effect on the liver and lung according to serological detection and histopathology. As part of the preclinical studies, our results provide acute toxicity and mutagenicity evaluation of the promising analgesic conotoxin lt14a."

Journal • Preclinical • CNS Disorders • Epilepsy • Pain

Mass spectrometric identification and denovo sequencing of novel conotoxins from vermivorous cone snail (Conus inscriptus), and preliminary screening of its venom for biological activities in vitro and in vivo. (PubMed, Saudi J Biol Sci) - "Among them, amino acid sequences of 11 novel conopeptides with one, two and three disulfides belonging to different classes were derived through manual de novo sequencing. The anticonvulsant study of natural venom effectively reduced the locomotor activity against pentylenetetrazole (PTZ) treated zebrafish. This concludes that the venom peptides from Conus inscriptus exhibit potential anticonvulsant function, which leads to the discovery of lead molecules against seizures."

Journal • Preclinical • CNS Disorders

Post-translationally modified conopeptides: Biological activities and pharmacological applications. (PubMed, Peptides) - "Various conopeptides reveal post-translational modifications of specific amino acids, such as hydroxylation of proline and lysine, gamma-carboxylation of glutamate, formation of N-terminal pyroglutamate, isomerization of L- to D-amino acid, bromination of tryptophan, O-glycosylation of threonine or serine, sulfation of tyrosine, and cysteinylation of cysteine, other than the more common disulfide crosslinking and C-terminal amidation. Many of the post-translationally modified peptides paved the way for the characterization, by alternative analytical methods, of other pharmacologically important peptides that are classified under 27 conopeptide families denoting pharmacological classes."

Journal • Review • Cardiovascular • CNS Disorders • Epilepsy • Myocardial Infarction • Pain

The first Conus genome assembly reveals a primary genetic central dogma of conopeptides in C. betulinus. (PubMed, Cell Discov) - "Variable peptide processing at the proteomic level, generating a big diversity of venom conopeptides with alternative cleavage sites, post-translational modifications, and N-/C-terminal truncations, may explain how the 133 genes and ~123 transcripts can generate thousands of conopeptides in the venom of individual C. betulinus. We also predicted many conopeptides with high stereostructural similarities to the putative analgesic ω-MVIIA, addiction therapy AuIB and insecticide ImI, suggesting that our current genome assembly for C. betulinus is a valuable genetic resource for high-throughput prediction and development of potential pharmaceuticals."

Journal • CNS Disorders • Pain • Psychiatry

Discovery and Characterization of the Novel Conotoxin Lv1d from Conus lividus that Presents Analgesic Activity. (PubMed, Toxicon) - "The cDNA of Lv1c encodes a 65 residue conopeptide precursor, which consists of a 21 residue signal peptide, a 27 residue Pro region, and 17 residues of mature peptide...In conclusion, the synthesis of Lv1d and its biological and physiological data might contribute to the development of this peptide as a novel potential drug for therapeutic applications. This finding also expands the knowledge of the targeting mechanism of the α4/7-subfamily conotoxins."

Journal • Pain

Conus venom fractions inhibit the adhesion of Plasmodium falciparum erythrocyte membrane protein 1 domains to the host vascular receptors. (PubMed, J Proteomics) - "This immense biomolecular library of conopeptides can be explored for potential use as therapeutic leads against persistent and emerging diseases affecting non-excitable systems...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."

Journal • Human Immunodeficiency Virus • Infectious Disease • Malaria • Novel Coronavirus Disease

Medicinal chemistry, pharmacology, and therapeutic potential of α-conotoxins antagonizing the α9α10 nicotinic acetylcholine receptor. (PubMed, Pharmacol Ther) - "Despite dissimilarities in their amino acid sequence and structures, these conopeptides are potent antagonists of the α9α10 nAChR subtype...The resulting synthetic analogues have not only functioned as molecular probes to explore ligand binding sites of the α9α10 nAChR, but also have the potential to become candidates for drug development. From the perspectives of medicinal chemistry and pharmacology, we highlight the structure and function of the α9α10 nAChR and review studies of α-conotoxins targeting it, including their three-dimensional structures, structure optimization strategies, and binding modes at the α9α10 nAChR, as well as their therapeutic potential."

Journal • Review • Breast Cancer • Neuralgia • Oncology • Pain • Peripheral Neuropathic Pain • Solid Tumor

Human health and snails. (PubMed, J Immunoassay Immunochem) - "Snail bioactive compounds like ω-MVIIA, μ-SIIIA, μO-MrVIB, Xen2174, δ-EVIA, α-Vc1.1, σ-GVIIA, Conantokin-G, and Contulakin-G, conopeptides can be used for the development of anti-cancer drugs. These compounds target the innate immunity and improve the defense system of humans and provide protection against these life-threatening health concerns. AbbreviationsFDA: Food and Drug Administration; UTI: urinal tract infection; nAChRs: nicotinic acetylcholine receptors; NMDA: N-methyl-D-aspartate; CNS: central nervous system; CAR T: chimeric antigen receptors therapy; Micro RNA: micro ribonucleic acid."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Dermatology • Oncology • Post-traumatic Stress Disorder

Identification of Conomarphin Variants in the Conus eburneus Venom and the Effect of Sequence and PTM Variations on Conomarphin Conformations. (PubMed, Mar Drugs) - "Furthermore, these predicted structures are pH sensitive, becoming more spherical and compact at higher pH. The subtle conformational variations observed here might play an important role in the selection and binding of the peptides to their molecular targets."

Journal

Conformational ensembles of non-peptide ω-conotoxin mimetics and Ca ion binding to human voltage-gated N-type calcium channel Ca2.2. (PubMed, Comput Struct Biotechnol J) - "A significant reduction in the tunnel volume at the selectivity filter and its enhancement at the activation gate of Ca-bound Ca2.2 suggests that ion binding modulates the outward splaying of pore-lining S6 helices to open the voltage gate. Overall, current study delineates dynamic conformational ensembles in terms of Ca ion and MVIIA-associated structural implications in the Ca2.2 that may help in better therapeutic intervention to chronic and neuropathic pain management."

Journal • Neuralgia • Pain • Peripheral Neuropathic Pain

Diversity of Conopeptides and Their Precursor Genes of Conus Litteratus. (PubMed, Mar Drugs) - "Gene cloning indicated that there was no intron in conotoxins of the B1- or J superfamily, one intron with 1273-1339 bp existed in a mature region of the F superfamily, which is different from the previously reported gene structure of conotoxins from other superfamilies. This study will enhance our understanding of conotoxin diversity, and the new conotoxins discovered in this paper will provide more potential candidates for the development of pharmacological probes and marine peptide drugs."

Journal

ConoMode, a database for conopeptide binding modes. (PubMed, Database (Oxford)) - "Furthermore, the database is fully optimized for unstructured data and flexible data models. Database URL: http://conomode.qnlm.ac/conomode/conomode/index."

Journal

Conus coronatus and Conus frigidus Venom: A New Source of Conopeptides with Analgesic Activity. (PubMed, Avicenna J Med Biotechnol) - "LC-ESI-MS analysis of the fractions showed that the conotoxins of the analgesic fraction had molecular weights not previously reported. The findings give insight into the venom of two previously under-investigated Conus species and reveal the therapeutic potential of the containing conopeptides."

Journal • Pain

An integrative approach to the facile functional classification of dorsal root ganglion neuronal subclasses. (PubMed, Proc Natl Acad Sci U S A) - "RIIIJ effects were replicated by application of the K1.1 selective antagonist, Dendrotoxin-K, in several L-DRG subclasses (L1, L2, L3, and L5), suggesting the presence of functional K1.1/K1.2 heteromeric channels. Using this approach on other neuronal subclasses should ultimately accelerate the comprehensive classification and characterization of individual somatosensory neuronal subclasses within a mixed population."

Journal

Conopeptide-Functionalized Nanoparticles Selectively Antagonize Extrasynaptic N-Methyl-d-aspartate Receptors and Protect Hippocampal Neurons from Excitotoxicity In Vitro. (PubMed, ACS Nano) - "Additionally, we show that conopeptide-functionalized AuNPs are neuroprotective in an in vitro model of excitotoxicity. By using AuNPs carrying different allosteric inhibitors with distinct NMDAR subtype selectivity such as peptide conantokin-G or peptide conantokin-R, we suggest activation of extrasynaptic GluN2B-containing diheteromeric NMDARs as the main cause of excitotoxicity."

Journal • Preclinical • CNS Disorders