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  1. Article ; Online: Neuroprotective and cardioprotective conopeptides: an emerging class of drug leads.

    Twede, Vernon D / Miljanich, George / Olivera, Baldomero M / Bulaj, Grzegorz

    Current opinion in drug discovery & development

    2009  Volume 12, Issue 2, Page(s) 231–239

    Abstract: The peptides in the venoms of predatory marine snails belonging to the genus Conus ('cone snails') have well-established therapeutic applications for the treatment of pain and epilepsy. This review discusses the neuroprotective and cardioprotective ... ...

    Abstract The peptides in the venoms of predatory marine snails belonging to the genus Conus ('cone snails') have well-established therapeutic applications for the treatment of pain and epilepsy. This review discusses the neuroprotective and cardioprotective potential of four families of Conus peptides (conopeptides), including omega-conotoxins that target voltage-gated Ca2+ channels, conantokins that target NMDA receptors, mu-conotoxins that target voltage-gated Na+ channels, and kappa- and kappaM-conotoxins that target K+ channels. The diversity of Conus peptides that have already been shown to exhibit neuroprotective/cardioprotective activity suggests that marine snail venoms are a potentially rich source of drug leads with diverse mechanisms.
    MeSH term(s) Animals ; Calcium Channel Blockers/pharmacology ; Cardiovascular Agents/chemistry ; Cardiovascular Agents/isolation & purification ; Cardiovascular Agents/pharmacology ; Conotoxins/chemistry ; Conotoxins/isolation & purification ; Conotoxins/pharmacology ; Drug Discovery ; Excitatory Amino Acid Antagonists/pharmacology ; Humans ; Neuroprotective Agents/chemistry ; Neuroprotective Agents/isolation & purification ; Neuroprotective Agents/pharmacology ; Potassium Channel Blockers/pharmacology ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors ; Sodium Channel Blockers/pharmacology ; Structure-Activity Relationship ; omega-Conotoxins/pharmacology
    Chemical Substances Calcium Channel Blockers ; Cardiovascular Agents ; Conotoxins ; Excitatory Amino Acid Antagonists ; Neuroprotective Agents ; Potassium Channel Blockers ; Receptors, N-Methyl-D-Aspartate ; Sodium Channel Blockers ; omega-Conotoxins
    Language English
    Publishing date 2009-03-31
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 1461136-3
    ISSN 2040-3437 ; 1367-6733
    ISSN (online) 2040-3437
    ISSN 1367-6733
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5276: Show issues Location:
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  2. Article ; Online: From molecular phylogeny towards differentiating pharmacology for NMDA receptor subtypes.

    Platt, Randall J / Curtice, Kigen J / Twede, Vernon D / Watkins, Maren / Gruszczyński, Paweł / Bulaj, Grzegorz / Horvath, Martin P / Olivera, Baldomero M

    Toxicon : official journal of the International Society on Toxinology

    2014  Volume 81, Page(s) 67–79

    Abstract: In order to decode the roles that N-methyl-D-aspartate (NMDA) receptors play in excitatory neurotransmission, synaptic plasticity, and neuropathologies, there is need for ligands that differ in their subtype selectivity. The conantokin family of Conus ... ...

    Abstract In order to decode the roles that N-methyl-D-aspartate (NMDA) receptors play in excitatory neurotransmission, synaptic plasticity, and neuropathologies, there is need for ligands that differ in their subtype selectivity. The conantokin family of Conus peptides is the only group of peptidic natural products known to target NMDA receptors. Using a search that was guided by phylogeny, we identified new conantokins from the marine snail Conus bocki that complement the current repertoire of NMDA receptor pharmacology. Channel currents measured in Xenopus oocytes demonstrate conantokins conBk-A, conBk-B, and conBk-C have highest potencies for NR2D containing receptors, in contrast to previously characterized conantokins that preferentially block NR2B containing NMDA receptors. Conantokins are rich in γ-carboxyglutamate, typically 17-34 residues, and adopt helical structure in a calcium-dependent manner. As judged by CD spectroscopy, conBk-C adopts significant helical structure in a calcium ion-dependent manner, while calcium, on its own, appears insufficient to stabilize helical conformations of conBk-A or conBk-B. Molecular dynamics simulations help explain the differences in calcium-stabilized structures. Two-dimensional NMR spectroscopy shows that the 9-residue conBk-B is relatively unstructured but forms a helix in the presence of TFE and calcium ions that is similar to other conantokin structures. These newly discovered conantokins hold promise that further exploration of small peptidic antagonists will lead to a set of pharmacological tools that can be used to characterize the role of NMDA receptors in nervous system function and disease.
    MeSH term(s) Amino Acid Sequence ; Animals ; Base Sequence ; Circular Dichroism ; Conotoxins/chemistry ; Conus Snail/chemistry ; Ligands ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Sequence Data ; Mollusk Venoms/chemistry ; Patch-Clamp Techniques ; Phylogeny ; Rats ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate/chemistry ; Synaptic Transmission/drug effects ; Xenopus
    Chemical Substances Conotoxins ; Ligands ; Mollusk Venoms ; Receptors, N-Methyl-D-Aspartate
    Language English
    Publishing date 2014-02-07
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 204479-1
    ISSN 1879-3150 ; 0041-0101
    ISSN (online) 1879-3150
    ISSN 0041-0101
    DOI 10.1016/j.toxicon.2014.01.016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 501: Show issues Location:
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  3. Article ; Online: Characterization of conantokin Rl-A: molecular phylogeny as structure/function study.

    Gowd, Konkallu H / Watkins, Maren / Twede, Vernon D / Bulaj, Grzegorz W / Olivera, Baldomero M

    Journal of peptide science : an official publication of the European Peptide Society

    2010  Volume 16, Issue 8, Page(s) 375–382

    Abstract: A multidisciplinary strategy for discovery of new Conus venom peptides combines molecular genetics and phylogenetics with peptide chemistry and neuropharmacology. Here we describe application of this approach to the conantokin family of conopeptides ... ...

    Abstract A multidisciplinary strategy for discovery of new Conus venom peptides combines molecular genetics and phylogenetics with peptide chemistry and neuropharmacology. Here we describe application of this approach to the conantokin family of conopeptides targeting NMDA receptors. A new conantokin from Conus rolani, ConRl-A, was identified using molecular phylogeny and subsequently synthesized and functionally characterized. ConRl-A is a 24-residue peptide containing three gamma-carboxyglutamic acid residues with a number of unique sequence features compared to conantokins previously characterized. The HPLC elution of ConRl-A suggested that this peptide exists as two distinct, slowly exchanging conformers. ConRl-A is predominantly helical (estimated helicity of 50%), both in the presence and absence of Ca(++). The order of potency for blocking the four NMDA receptor subtypes by ConRl-A was NR2B > NR2D > NR2A > NR2C. This peptide has a greater discrimination between NR2B and NR2C than any other ligand reported so far. In summary, ConRl-A is a new member of the conantokin family that expands our understanding of structure/function of this group of peptidic ligands targeted to NMDA receptors. Thus, incorporating phylogeny in the discovery of novel ligands for the given family of ion channels or receptors is an efficient means of exploring the megadiverse group of peptides from the genus Conus.
    MeSH term(s) Animals ; Circular Dichroism ; Conotoxins/genetics ; Conotoxins/metabolism ; Conus Snail/classification ; Conus Snail/metabolism ; DNA, Complementary ; Electrophysiology ; Mollusk Venoms/metabolism ; Oocytes ; Peptides/genetics ; Peptides/metabolism ; Phylogeny ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors ; Xenopus
    Chemical Substances Conotoxins ; DNA, Complementary ; Mollusk Venoms ; Peptides ; Receptors, N-Methyl-D-Aspartate
    Language English
    Publishing date 2010-06-22
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1234416-3
    ISSN 1099-1387 ; 1075-2617
    ISSN (online) 1099-1387
    ISSN 1075-2617
    DOI 10.1002/psc.1249
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6200: Show issues Location:
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  4. Article ; Online: Defining modulatory inputs into CNS neuronal subclasses by functional pharmacological profiling.

    Raghuraman, Shrinivasan / Garcia, Alfredo J / Anderson, Tatiana M / Twede, Vernon D / Curtice, Kigen J / Chase, Kevin / Ramirez, Jan-Marino / Olivera, Baldomero M / Teichert, Russell W

    Proceedings of the National Academy of Sciences of the United States of America

    2014  Volume 111, Issue 17, Page(s) 6449–6454

    Abstract: Previously we defined neuronal subclasses within the mouse peripheral nervous system using an experimental strategy called "constellation pharmacology." Here we demonstrate the broad applicability of constellation pharmacology by extending it to the CNS ... ...

    Abstract Previously we defined neuronal subclasses within the mouse peripheral nervous system using an experimental strategy called "constellation pharmacology." Here we demonstrate the broad applicability of constellation pharmacology by extending it to the CNS and specifically to the ventral respiratory column (VRC) of mouse brainstem, a region containing the neuronal network controlling respiratory rhythm. Analysis of dissociated cells from this locus revealed three major cell classes, each encompassing multiple subclasses. We broadly analyzed the combinations (constellations) of receptors and ion channels expressed within VRC cell classes and subclasses. These were strikingly different from the constellations of receptors and ion channels found in subclasses of peripheral neurons from mouse dorsal root ganglia. Within the VRC cell population, a subset of dissociated neurons responded to substance P, putatively corresponding to inspiratory pre-Bötzinger complex (preBötC) neurons. Using constellation pharmacology, we found that these substance P-responsive neurons also responded to histamine, and about half responded to bradykinin. Electrophysiological studies conducted in brainstem slices confirmed that preBötC neurons responsive to substance P exhibited similar responsiveness to bradykinin and histamine. The results demonstrate the predictive utility of constellation pharmacology for defining modulatory inputs into specific neuronal subclasses within central neuronal networks.
    MeSH term(s) Animals ; Bradykinin/pharmacology ; Brain Stem/cytology ; Brain Stem/drug effects ; Brain Stem/physiology ; Calcium/metabolism ; Cells, Cultured ; Central Nervous System/cytology ; Cluster Analysis ; Female ; Ganglia, Spinal/cytology ; Ganglia, Spinal/drug effects ; Ganglia, Spinal/physiology ; Histamine/pharmacology ; Imaging, Three-Dimensional ; Male ; Mice ; Mice, Inbred C57BL ; Nerve Net/cytology ; Nerve Net/drug effects ; Nerve Net/physiology ; Neurons/drug effects ; Neurons/physiology ; Receptors, Cholinergic/metabolism ; Receptors, Glutamate/metabolism ; Respiratory Center/cytology ; Substance P/pharmacology
    Chemical Substances Receptors, Cholinergic ; Receptors, Glutamate ; Substance P (33507-63-0) ; Histamine (820484N8I3) ; Bradykinin (S8TIM42R2W) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2014-04-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1404421111
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1148: Show issues Location:
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  5. Article ; Online: Conantokin-Br from Conus brettinghami and selectivity determinants for the NR2D subunit of the NMDA receptor.

    Twede, Vernon D / Teichert, Russell W / Walker, Craig S / Gruszczyński, Paweł / Kaźmierkiewicz, Rajmund / Bulaj, Grzegorz / Olivera, Baldomero M

    Biochemistry

    2009  Volume 48, Issue 19, Page(s) 4063–4073

    Abstract: Conantokins are venom peptides from marine cone snails that are NMDA receptor antagonists. Here, we report the characterization of a 24 AA conantokin from Conus brettinghami Coomans , H. E. , Moolenbeek , R. G. and Wils , E. ( 1982 ) Basteria 46 ( 1/4 ), ...

    Abstract Conantokins are venom peptides from marine cone snails that are NMDA receptor antagonists. Here, we report the characterization of a 24 AA conantokin from Conus brettinghami Coomans , H. E. , Moolenbeek , R. G. and Wils , E. ( 1982 ) Basteria 46 ( 1/4 ), 3 - 67 , conantokin-Br (con-Br), the first conantokin that does not have the conserved glutamate residue at position 2. Molecular modeling studies suggest that con-Br has a helical structure between residues 2-13. In contrast to other characterized conantokins, con-Br has a high potency for NMDA receptors with NR2D subunits. To identify determinants for NR2D potency, we synthesized chimeras of con-Br and conantokin-R (con-R); the latter has a approximately 30-fold lower potency for the NR2D subtype. The characterization of two reciprocal chimeras (con-Br/R and con-R/Br), comprising the first 9-10 N-terminal AAs of each conantokin followed by the corresponding C-terminal AAs of the other conantokin demonstrates that determinants for NR2D selectivity are at the N-terminal region. Additional analogues comprising 1-3 amino acid substitutions from each peptide into the homologous region of the other led to the identification of a key determinant; a Tyr residue in position 5 increases potency for NR2D, while Val at this locus causes a decrease. The systematic definition of key determinants in the conantokin peptides for NMDA receptor subtype selectivity is an essential component in the development of conantokin peptides that are highly selective for each specific NMDA receptor subtype.
    MeSH term(s) Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Computer Simulation ; Conotoxins/chemistry ; Conotoxins/metabolism ; Conotoxins/pharmacology ; Conus Snail/chemistry ; Electrophysiology ; Female ; Inhibitory Concentration 50 ; Models, Molecular ; Molecular Sequence Data ; Oocytes/metabolism ; Oxidation-Reduction ; Patch-Clamp Techniques ; Peptides/chemistry ; Peptides/metabolism ; Peptides/pharmacology ; Perfusion ; Protein Folding ; Protein Structure, Secondary ; Protein Subunits/metabolism ; Protein Subunits/pharmacology ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate/chemistry ; Receptors, N-Methyl-D-Aspartate/metabolism ; Sequence Homology, Amino Acid ; Structure-Activity Relationship ; Tyrosine/metabolism ; Xenopus
    Chemical Substances Conotoxins ; Peptides ; Protein Subunits ; Receptors, N-Methyl-D-Aspartate ; conantokin-Br, Conus brettinghami ; Tyrosine (42HK56048U)
    Language English
    Publishing date 2009-03-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/bi802259a
    Database MEDical Literature Analysis and Retrieval System OnLINE

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