A5061587018- Nicotinic Acetylcholine Receptors Study
- Receptor Mechanisms and Signaling
- Ion channel regulation and function
- Sphingolipid Metabolism and Signaling
- Neuropeptides and Animal Physiology
- Chemical Synthesis and Analysis
- Protein Kinase Regulation and GTPase Signaling
- Neuroscience and Neuropharmacology Research
- PI3K/AKT/mTOR signaling in cancer
- Asymmetric Synthesis and Catalysis
- Lipid Membrane Structure and Behavior
- Neurobiology and Insect Physiology Research
- Marine Toxins and Detection Methods
- Cholinesterase and Neurodegenerative Diseases
- Asymmetric Hydrogenation and Catalysis
- Antimicrobial Peptides and Activities
- ATP Synthase and ATPases Research
- Chemical Synthesis and Reactions
- Cellular transport and secretion
- Organic and Inorganic Chemical Reactions
- Synthetic Organic Chemistry Methods
- Cancer, Lipids, and Metabolism
- Synthesis and Biological Activity
- Neuroendocrine regulation and behavior
- Insect and Pesticide Research
University of Utah
2015-2024
University of Pennsylvania
2012
University of Tennessee Health Science Center
2008
University of Colorado Health
2006
University of Warsaw
2003-2005
Warsaw University of Technology
2004
More than 100 species of venomous cone snails (genus Conus) are highly effective predators fish. The vast majority venom components identified and functionally characterized to date neurotoxins specifically targeted receptors, ion channels, transporters in the nervous system prey, predators, or competitors. Here we describe a component targeting energy metabolism, radically different mechanism. Two fish-hunting snails, Conus geographus tulipa, have evolved specialized insulins that expressed...
Abstract Signal transduction modifiers that modulate the lysophosphatidic acid (LPA) pathway have potential as anticancer agents. Herein, we describe metabolically stabilized LPA analogues reduce cell migration and invasion cause regression of orthotopic breast tumors in vivo. Two diastereoisomeric α-bromophosphonates (BrP-LPA) were synthesized, pharmacology was determined for five G protein–coupled receptors (GPCRs). The syn anti diastereomers BrP-LPA are pan-LPA GPCR antagonists also...
Significance This study addresses the need to phase out opioids as major analgesic drugs for moderate severe chronic pain. We establish that a highly selective and potent inhibitor of α9α10 nicotinic acetylcholine receptor (nAChR) subtype prevents expression chemotherapy-induced neuropathic Thus, antagonists nAChR are potential leads nonopioid drug development. The effects inhibitors receptor, together with genetic studies, suggest key role in an intercellular signaling network can be...
Voltage-gated sodium channels (VGSCs) are important for action potentials. There seven major isoforms of the pore-forming and gate-bearing α-subunit (Na V 1) VGSCs in mammalian neurons, a given neuron can express more than one isoform. Five neuronal isoforms, Na 1.1, 1.2, 1.3, 1.6, 1.7, exquisitely sensitive to tetrodotoxin (TTX), functional differentiation these presents serious challenge. Here, we examined panel 11 μ-conopeptides their ability block rodent 1.1 through 1.8 expressed Xenopus...
The fish-hunting marine cone snail Conus geographus uses a specialized venom insulin to induce hypoglycemic shock in its prey. We recently showed that this insulin, Con-Ins G1, has unique characteristics relevant the design of new therapeutics. Here, we show snails provide rich source minimized ligands vertebrate receptor. Insulins from C. , tulipa and kinoshitai exhibit diverse sequences, yet all bind activate human Molecular dynamics reveal modes action are distinct any other insulins...
Isoform-selective agonists and antagonists of the lysophosphatidic acid (LPA) G-protein-coupled receptors (GPCRs) have important potential applications in cell biology therapy. LPA GPCRs regulate cancer proliferation, invasion, angiogenesis, biochemical resistance to chemotherapy- radiotherapy-induced apoptosis. its analogues are also feedback inhibitors enzyme lysophospholipase D (lysoPLD, known as autotaxin), a central regulator invasion metastasis. For therapy, ideal therapeutic profile...
Voltage-gated sodium channels (VGSCs) are assembled from two classes of subunits, a pore-bearing α-subunit (NaV 1) and one or accessory β-subunits βs). Neurons in mammals can express more seven isoforms NaV 1 four β. The peptide μ-conotoxins, like the guanidinium alkaloids tetrodotoxin (TTX) saxitoxin (STX), inhibit VGSCs by blocking pore 1. Hitherto, effects β-subunit co-expression on activity these toxins have not been comprehensively assessed.Four μ-conotoxins (μ-TIIIA, μ-PIIIA, μ-SmIIIA...
Alan Kohn showed that two cone-snail species—Conus striatus Linnaeus, 1758, and Conus catus Hwass, 1792—hunt fish as their primary prey. In the seven decades since then, it has been established these species belong to subgenus Pionoconus Mörch, 1852, a well-defined lineage of one eight piscivorous clades. this review, an integrated multidisciplinary framework for biology is presented, based on numerous research papers published Kohn's seminal discovery. The molecular biology, phylogeny,...
A cone snail venom peptide, μO§-conotoxin GVIIJ from Conus geographus, has a unique posttranslational modification, S-cysteinylated cysteine, which makes possible formation of covalent tether peptide to its target Na channels at distinct ligand-binding site. is 35-aa with 7 cysteine residues; six the cysteines form 3 disulfide cross-links, and one (Cys24) S-cysteinylated. Due limited availability native GVIIJ, we primarily used synthetic analog whose Cys24 was S-glutathionylated (abbreviated...
Somatostatin (SS) is a peptide hormone with diverse physiological roles. By investigating deep-water clade of fish-hunting cone snails, we show that predator-prey evolution has generated set SS analogs, each optimized to elicit specific systemic effects in prey. The increased metabolic stability, distinct receptor activation profiles, and chemical diversity the venom analogs make them suitable leads for therapeutic application, including pain, cancer, endocrine disorders. Our findings not...
The oxidative folding of large polypeptides has been investigated in detail; however, comparatively little is known about the enzyme-assisted small, disulfide-containing peptide substrates. To investigate concerted effect multiple enzymes on small disulfide-rich peptides, we sequenced and expressed protein-disulfide isomerase (PDI), peptidyl-prolyl cis-trans isomerase, immunoglobulin-binding protein (BiP) from Conus venom glands. PDI was shown to catalyze oxidation reduction disulfide bonds...
Nicotinic acetylcholine receptors (nAChRs) containing α6 and β2 subunits modulate dopamine release in the basal ganglia are therapeutically relevant targets for treatment of neurological psychiatric disorders including Parkinson9s disease nicotine dependence. However, expression profile β4 overlap a variety tissues locus ceruleus, retina, hippocampus, dorsal root ganglia, adrenal chromaffin cells. Ligands that bind α6β2 nAChRs also potently closely related α6β4 subtype. To distinguish...
Venom-derived compounds are of broad interest in neuropharmacology and drug development. α-Conotoxins small disulfide-containing peptides from
The spike-protein of SARS-CoV-2 has a distinctive amino-acid sequence (
Novel biomaterials have been prepared in which glycosaminoglycans (GAGs) are chemically modified to create amphiphilic multiblock copolymers that able adhere hydrophobic surfaces and can self-assemble into cross-linker-free hydrogels. First, the triblock poly(ethylene oxide)−polypropylene oxide (Pluronics) were converted previously unknown aminooxy (AO) derivatives. Both mono-AO bis-AO Pluronics (AOPs) synthesized fully characterized order prepare tetrablock pentablock copolymers,...
Adult rat dorsal root ganglion (DRG) neurons normally express transcripts for five isoforms of the α-subunit voltage-gated sodium channels: NaV 1.1, 1.6, 1.7, 1.8 and 1.9. Tetrodotoxin (TTX) readily blocks all but 1.9, pharmacological agents that discriminate among TTX-sensitive 1-isoforms are scarce. Recently, we used activity profile a panel μ-conotoxins in blocking cloned rodent expressed Xenopus laevis oocytes to conclude action potentials A- C-fibres sciatic nerve were, respectively,...
Among the μ-conotoxins that block vertebrate voltage-gated sodium channels (VGSCs), some have been shown to be potent analgesics following systemic administration in mice. We determined solution structure of a new representative this family, μ-BuIIIB, and established its disulfide connectivities by direct mass spectrometric collision induced dissociation fragmentation peptide with disulfides intact. The major oxidative folding product adopts 1-4/2-5/3-6 pattern bridges: Cys5-Cys17,...
We investigated the identities of isoforms α (NaV1)- and β (NaVβ)-subunits voltage-gated sodium channels, including those responsible for action potentials in rodent sciatic nerves. To examine α-subunits, we used seven μ-conotoxins, which target site 1 channel. With use exogenously expressed show that two μ-BuIIIB μ-SxIIIA, are 50-fold more potent blocking NaV1.6 from mouse than rat. Furthermore, observed μ-SxIIIA blockers large, myelinated A-fiber compound (A-CAPs) [but not small,...
Nicotinic acetylcholine receptors (nAChRs) containing α6 and β4 subunits are expressed by dorsal root ganglion neurons have been implicated in neuropathic pain. Rodent models often used to evaluate the efficacy of analgesic compounds, but species differences may affect activity some nAChR ligands. A previous candidate α-conotoxin-based therapeutic yielded promising results rodent models, failed human clinical trials, emphasizing importance understanding ligand activity. Here, we show that...