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  1. Article: A toxin-based approach to neuropeptide and peptide hormone discovery.

    Koch, Thomas Lund / Torres, Joshua P / Baskin, Robert P / Salcedo, Paula Flórez / Chase, Kevin / Olivera, Baldomero M / Safavi-Hemami, Helena

    Frontiers in molecular neuroscience

    2023  Volume 16, Page(s) 1176662

    Abstract: Peptide hormones and neuropeptides form a diverse class of bioactive secreted molecules that control essential processes in animals. Despite breakthroughs in peptide discovery, many signaling peptides remain undiscovered. Recently, we demonstrated the ... ...

    Abstract Peptide hormones and neuropeptides form a diverse class of bioactive secreted molecules that control essential processes in animals. Despite breakthroughs in peptide discovery, many signaling peptides remain undiscovered. Recently, we demonstrated the use of somatostatin-mimicking toxins from cone snails to identify the invertebrate ortholog of somatostatin. Here, we show that this toxin-based approach can be systematically applied to discover other unknown secretory peptides that are likely to have signaling function. Using large sequencing datasets, we searched for homologies between cone snail toxins and secreted proteins from the snails' prey. We identified and confirmed expression of five toxin families that share strong similarities with unknown secretory peptides from mollusks and annelids and in one case also from ecdysozoans. Based on several lines of evidence we propose that these peptides likely act as signaling peptides that serve important physiological functions. Indeed, we confirmed that one of the identified peptides belongs to the family of crustacean hyperglycemic hormone, a peptide not previously observed in Spiralia. We propose that this discovery pipeline can be broadly applied to other systems in which one organism has evolved molecules to manipulate the physiology of another.
    Language English
    Publishing date 2023-08-31
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2452967-9
    ISSN 1662-5099
    ISSN 1662-5099
    DOI 10.3389/fnmol.2023.1176662
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Venom-inspired somatostatin receptor 4 (SSTR4) agonists as new drug leads for peripheral pain conditions.

    Bjørn-Yoshimoto, Walden E / Ramiro, Iris Bea L / Koch, Thomas Lund / Engholm, Ebbe / Yeung, Ho Yan / Sørensen, Kasper K / Goddard, Carolyn M / Jensen, Kathrine L / Smith, Nicholas A / Martin, Laurent F / Smith, Brian J / Madsen, Kenneth L / Jensen, Knud J / Patwardhan, Amol / Safavi-Hemami, Helena

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Persistent pain affects one in five people worldwide, often with severely debilitating consequences. Current treatment options, which can be effective for mild or acute pain, are ill-suited for moderate-to-severe persistent pain, resulting in an urgent ... ...

    Abstract Persistent pain affects one in five people worldwide, often with severely debilitating consequences. Current treatment options, which can be effective for mild or acute pain, are ill-suited for moderate-to-severe persistent pain, resulting in an urgent need for new therapeutics. In recent years, the somatostatin receptor 4 (SSTR
    One sentence summary: Venom peptides from predatory marine mollusks provide new leads for treating peripheral pain conditions through a non-opioid target.
    Language English
    Publishing date 2024-04-30
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.04.29.591104
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A previously unrecognized superfamily of macro-conotoxins includes an inhibitor of the sensory neuron calcium channel Cav2.3.

    Hackney, Celeste M / Flórez Salcedo, Paula / Mueller, Emilie / Koch, Thomas Lund / Kjelgaard, Lau D / Watkins, Maren / Zachariassen, Linda G / Tuelung, Pernille Sønderby / McArthur, Jeffrey R / Adams, David J / Kristensen, Anders S / Olivera, Baldomero / Finol-Urdaneta, Rocio K / Safavi-Hemami, Helena / Morth, Jens Preben / Ellgaard, Lars

    PLoS biology

    2023  Volume 21, Issue 8, Page(s) e3002217

    Abstract: Animal venom peptides represent valuable compounds for biomedical exploration. The venoms of marine cone snails constitute a particularly rich source of peptide toxins, known as conotoxins. Here, we identify the sequence of an unusually large conotoxin, ... ...

    Abstract Animal venom peptides represent valuable compounds for biomedical exploration. The venoms of marine cone snails constitute a particularly rich source of peptide toxins, known as conotoxins. Here, we identify the sequence of an unusually large conotoxin, Mu8.1, which defines a new class of conotoxins evolutionarily related to the well-known con-ikot-ikots and 2 additional conotoxin classes not previously described. The crystal structure of recombinant Mu8.1 displays a saposin-like fold and shows structural similarity with con-ikot-ikot. Functional studies demonstrate that Mu8.1 curtails calcium influx in defined classes of murine somatosensory dorsal root ganglion (DRG) neurons. When tested on a variety of recombinantly expressed voltage-gated ion channels, Mu8.1 displayed the highest potency against the R-type (Cav2.3) calcium channel. Ca2+ signals from Mu8.1-sensitive DRG neurons were also inhibited by SNX-482, a known spider peptide modulator of Cav2.3 and voltage-gated K+ (Kv4) channels. Our findings highlight the potential of Mu8.1 as a molecular tool to identify and study neuronal subclasses expressing Cav2.3. Importantly, this multidisciplinary study showcases the potential of uncovering novel structures and bioactivities within the largely unexplored group of macro-conotoxins.
    MeSH term(s) Mice ; Animals ; Conotoxins/pharmacology ; Conotoxins/chemistry ; Calcium Channels ; Peptides/chemistry ; Sensory Receptor Cells/metabolism ; Snails
    Chemical Substances Conotoxins ; Calcium Channels ; Peptides
    Language English
    Publishing date 2023-08-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2126776-5
    ISSN 1545-7885 ; 1544-9173
    ISSN (online) 1545-7885
    ISSN 1544-9173
    DOI 10.1371/journal.pbio.3002217
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Reconstructing the Origins of the Somatostatin and Allatostatin-C Signaling Systems Using the Accelerated Evolution of Biodiverse Cone Snail Toxins.

    Koch, Thomas Lund / Ramiro, Iris Bea L / Flórez Salcedo, Paula / Engholm, Ebbe / Jensen, Knud Jørgen / Chase, Kevin / Olivera, Baldomero M / Bjørn-Yoshimoto, Walden Emil / Safavi-Hemami, Helena

    Molecular biology and evolution

    2022  Volume 39, Issue 4

    Abstract: Somatostatin and its related peptides (SSRPs) form an important family of hormones with diverse physiological roles. The ubiquitous presence of SSRPs in vertebrates and several invertebrate deuterostomes suggests an ancient origin of the SSRP signaling ... ...

    Abstract Somatostatin and its related peptides (SSRPs) form an important family of hormones with diverse physiological roles. The ubiquitous presence of SSRPs in vertebrates and several invertebrate deuterostomes suggests an ancient origin of the SSRP signaling system. However, the existence of SSRP genes outside of deuterostomes has not been established, and the evolutionary history of this signaling system remains poorly understood. Our recent discovery of SSRP-like toxins (consomatins) in venomous marine cone snails (Conus) suggested the presence of a related signaling system in mollusks and potentially other protostomes. Here, we identify the molluscan SSRP-like signaling gene that gave rise to the consomatin family. Following recruitment into venom, consomatin genes experienced strong positive selection and repeated gene duplications resulting in the formation of a hyperdiverse family of venom peptides. Intriguingly, the largest number of consomatins was found in worm-hunting species (>400 sequences), indicating a homologous system in annelids, another large protostome phylum. Consistent with this, comprehensive sequence mining enabled the identification of SSRP-like sequences (and their corresponding orphan receptor) in annelids and several other protostome phyla. These results established the existence of SSRP-like peptides in many major branches of bilaterians and challenge the prevailing hypothesis that deuterostome SSRPs and protostome allatostatin-C are orthologous peptide families. Finally, having a large set of predator-prey SSRP sequences available, we show that although the cone snail's signaling SSRP-like genes are under purifying selection, the venom consomatin genes experience rapid directional selection to target receptors in a changing mix of prey.
    MeSH term(s) Animals ; Conotoxins/genetics ; Conus Snail/genetics ; Neuropeptides ; Peptides/genetics ; Somatostatin/genetics ; Venoms
    Chemical Substances Conotoxins ; Neuropeptides ; Peptides ; Venoms ; allatostatin (110119-33-0) ; Somatostatin (51110-01-1)
    Language English
    Publishing date 2022-04-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 998579-7
    ISSN 1537-1719 ; 0737-4038
    ISSN (online) 1537-1719
    ISSN 0737-4038
    DOI 10.1093/molbev/msac075
    Database MEDical Literature Analysis and Retrieval System OnLINE

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