eBriefing

Venomics: Drug Discovery from Nature's Deadliest

Venomics
Reported by
Nicholette Zeliadt

Posted February 19, 2014

Presented By

Hot Topics in Life Sciences

Overview

The deadly cocktails produced by venomous animals such as spiders, snakes, sea snails, and leeches contain many compounds that act on vital systems in their prey. Thus, venoms have enormous therapeutic potential as drugs or as tools for drug development. A few peptides isolated from snake and cone snail venoms have been developed and approved as drugs. Based on this success, pharmaceutical companies are investing in venom-based drug discovery programs. However, most currently approved products were developed from easily accessible snake venom proteins with cardiovascular specificities. New technologies are opening the field; analgesics, anti-tumor agents, and even agricultural pesticides await discovery as researchers begin mining the venoms of the more than 170 000 species that have yet to be explored.

Venomics—an integrated approach combining genomic, proteomic, and transcriptomic data—aims to characterize this immense and largely untapped reservoir of molecules and to understand the evolutionary history of venoms and venomous animals. This research is made possible by recent advances in mass spectrometry and next-generation sequencing technologies that enable high-throughput analyses of venoms. On November 4, 2013, researchers gathered at the New York Academy of Sciences for a Hot Topics in Life Sciences symposium titled Venomics: Drug Discovery from Natures Deadliest. The symposium focused on recent discoveries in venomics, tools and strategies for venom analyses, and future goals for the study of bioactive compounds in venoms.

Use the tabs above to find a meeting report and multimedia from this event.

Presentations available from:
Anirban Banerjee, PhD (National Institute of Child Health and Human Development, NIH)
Carole A. Bewley, PhD (National Institute of Diabetes and Digestive and Kidney Diseases, NIH)
Pierre Escoubas, PhD (VenomeTech)
Bryan Fry, PhD (The University of Queensland, Australia)
Mandë Holford, PhD (Hunter College, CUNY; American Museum of Natural History)
Baldomero M. Olivera, PhD (University of Utah)
Mark E. Siddall, PhD (American Museum of Natural History)
Beatrix Ueberheide, PhD (NYU Langone Medical Center)


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Resources

Conus venom peptides

Clark C, Olivera BM, Cruz LJ. A toxin from the venom of the marine snail Conus geographus which acts on the vertebrate central nervous system. Toxicon. 1981;19(5):691-9.

McIntosh M, Cruz LJ, Hunkapiller MW, et al. Isolation and structure of a peptide toxin from the marine snail Conus magus. Arch Biochem Biophys. 1982;218(1):329-34.

Olivera BM. Conus peptides: biodiversity-based discovery and exogenomics. J Biol Chem. 2006;281(42):31173-7.

Olivera BM, Cruz LJ, Desantos V, et al. Neuronal calcium-channel antagonistsdiscrimination between calcium-channel subtypes using omega-conotoxin from Conus magus venom. Biochemistry. 1987;26(8):2086-90.

Olivera BM, Rivier J, Clark C, et al. Diversity of Conus neuropeptides. Science. 1990;249(4966):257-63.

Olivera BM, Teichert RW. Diversity of the neurotoxic Conus peptides: a model for concerted pharmacological discovery. Mol Interv. 2007;7(5):251-60.

Seronay RA, Fedosov AE, Astilla MA, et al. Accessing novel conoidean venoms: Biodiverse lumun–lumun marine communities, an untapped biological and toxinological resource. Toxicon. 2010;56(7):1257-66.

Teichert RW, Raghuraman S, Memon T, et al. Characterization of two neuronal subclasses through constellation pharmacology. Proc Natl Acad Sci U S A. 2012;109(31):12758-63.

Terlau H, Olivera BM. Conus venoms: a rich source of novel ion channel-targeted peptides. Physiol Rev. 2004;84(1):41-68.

Watkins M, Hillyard DR, Olivera BM. Genes expressed in a turrid venom duct: divergence and similarity to conotoxins. J Mol Evol. 2006;62(3):247-56.

The Cone Snail
A website run by Olivera's lab at the University and Utah, with information and photographs of cone snails.

Cyanobacteria and viral infections

Bewley CA. Solution structure of a cyanovirin-N:Man alpha 1-2Man alpha complex: structural basis for high-affinity carbohydrate-mediated binding to gp120. Structure. 2001;9(10):931-40.

Bewley CA, Gustafson KR, Boyd MR, et al. Solution structure of cyanovirin-N, a potent HIV-inactivating protein. Nat Struct Biol. 1998;5(7):571-8.

Bewley CA, Otero-Quintero S. The potent anti-HIV protein cyanovirin-N contains two novel carbohydrate binding sites that selectively bind to Man(8) D1D3 and Man(9) with nanomolar affinity: implications for binding to the HIV envelope protein gp120. J Am Chem Soc. 2001;123(17):3892-902.

Boyd M, Gustafson KR, McMahon JB, et al. Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: potential applications to microbicide development. Antimicrob Agents Chemother. 1997;41(7):1521-30.

Helle F, Vieyres G, Elkrief L, et al. Role of N-linked glycans in the functions of hepatitis C virus envelope proteins incorporated into infectious virions. J Virol. 2010;84(22):11905-15.

Kachko A, Loesgen S, Shahzad-Il-Hussan S, et al. Inhibition of hepatitis C virus by the cyanobacterial protein microcystis viridis lectin: differences between the high-mannose specific lectins MVL, CV-N, and GNA. Mol Pharm. 2013;10(12):4590-602.

Teissier E, Penin F, Pcheur El. Targeting cell entry of enveloped viruses as an antiviral strategy. Molecules. 2010;16(1):221-50.

Venom evolution as a guide for biodiscovery

Ali SA, Baumann K, Jackson TN, et al. Proteomic comparison of Hypnale hypnale (Hump-Nosed Pit-Viper) and Calloselasma rhodostoma (Malay Pit-Viper) venoms. J Proteomics. 2013;91:338-43.

Fry BG. From genome to venome: molecular origin and evolution of the snake venom proteome inferred from phylogenetic analysis of toxin sequences and related body proteins. Genome Res. 2005;15(3):403-20.

Fry BG, Roelants K, Champagne DE, et al. The toxicogenomic multiverse: convergent recruitment of proteins into animal venoms. Annu Rev Genomics Hum Genet. 2009;10:483-511.

Fry BG, Wster W, Kini RM, et al. Molecular evolution and phylogeny of elapid snake venom three-finger toxins. J Mol Evol. 2003;57(1):110-29.

Mass spectrometry for the discovery of venomous compounds

Bern M, Cai Y, Goldberg D. Lookup peaks: a hybrid of de novo sequencing and database search for protein identification by tandem mass spectrometry. Anal Chem. 2007;79(4):1393-400.

Bhatia S, Kill YJ, Ueberheide B, et al. Constrained de novo sequencing of conotoxins. J Proteome Res. 2012;11(8):4191-200.

Karbat I, Turkov M, Cohen L, et al. X-ray structure and mutagenesis of the scorption depressant toxin LqhIT2 reveals key determinants crucial for activity and anti-insect selectivity. J Mol Biol. 2007;366(2):586-601.

Mikesh LM, Ueberheide B, Chi A, et al. The utility of ETD mass spectrometry in proteomic analysis. Biochim Biophys Acta. 2006;1764(12):1811-22.

Simon MD, Chu F, Racki LR, et al. The site-specific installation of methyl-lysine analogs into recombinant histones. Cell. 2007;128(5):1003-12.

Ueberheide BM, Feny D, Alewood PF, Chait BT. Rapid sensitive analysis of cysteine rich peptide venom components. Proc Natl Acad Sci U S A. 2009;106(17):6910-5.

Novel therapeutic peptides from venomous marine snails

Castelin M, Puillandre N, Kantor YI, et al. Macroevolution of venom apparatus innovations in auger snails (Gastropoda; Conoidea; Terebridae). Mol Phylogenet Evol. 2012;64(1):21-44.

Holford M, Puillandre N, Modica MV, et al. Correlating molecular phylogeny with venom apparatus occurrence in Panamic auger snails (Terebridae). PLoS One. 2009;4(11):e7667.

ONeil A, Reichhardt C, Johnson B, et al. Genetically programmed in vivo packaging of protein cargo and its controlled release from bacteriophage P22. Angew Chem Int Ed Engl. 2011;50(32):7425-8.

Puillandre N, Holford M. The Terebridae and teretoxins: Combining phylogeny and anatomy for the concerted discovery of bioactive compounds. BMC Chem Biol. 2010;10:7.

Vetter I, Davis JL, Rash LD, et al. Venomics: a new paradigm for natural products-based drug discovery. Amino Acids. 2011;40(1):15-28.

Wong HL, Wu XY, Bendayan R. Nanotechnological advances for the delivery of CNS therapeutics. Adv Drug Deliv Rev. 2012;64(7):686-700.

Mapping neurocircuits with venom toxins

Auer S, Ibañez-Tallon I. The King is dead: Checkmating ion channels with tethered toxins. Toxicon. 2010;56(8):1293-8.

Auer S, Strzebecher AS, Jüttner T, et al. Silencing neurotransmission with membrane-tethered toxins. Nat Methods. 2010;7(3):229-36.

Holford M, Auer S, Laqua M, Ibañez-Tallon I. Manipulating neuronal circuits with endogenous and recombinant cell-surface tethered modulators. Front Mol Neurosci. 2009;2:21.

Ibañez-Tallon I, Nitabach MN. Tethering toxins and peptide ligands for modulation of neuronal function. Curr Opin Neurobiol. 2012;22(1):72-8.

Ibañez-Tallon I, Wen H, Miwa JM, et al. Tethering naturally occurring peptide toxins for cell-autonomous modulation of ion channels and receptors in vivo. Neuron. 2004;43(3):305-11.

Strzebecher AS, Hu J, Smith ES, et al. An in vivo tethered toxin approach for the cell-autonomous inactivation of voltage-gated sodium channel currents. J Physiol. 2010;588(Pt 10):1695-707.

The atomic structure of a k channel–scorpion toxin complex

Banerjee A, Lee A, Campbell E, MacKinnon R. Structure of a pore-blocking toxin in complex with a eukaryotic voltage-dependent K(+) channel. Elife. 2013;2:e00594.

Long SB, Tao X, Campbell EB, MacKinnon R. Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature. 2007;450(7168)376-82.

MacKinnon R, Miller C. Mechanism of charybdotoxin block of the high-conductance, Ca2+-activated K+ channel. J Gen Physiol. 1988;91(3):335-49.

Tao X, MacKinnon R. Functional analysis of Kv1.2 and paddle chimera Kv channels in planar lipid bilayers. J Mol Biol. 2008;382(1):24-33.

Zhou Y, MacKinnon R. The occupancy of ions in the K+ selectivity filter: charge balance and coupling of ion binding to a protein conformational change underlie high conduction rates. J Mol Biol. 2003;333(5):965-75.

Evolutionary leech venomics

Borda E, Siddall ME. Arhynchobdellida (Annelida: Oligochaeta: Hirudinida): phylogenetic relationships and evolution. Mol Phylogenet Evol. 2004;30(1):213-25.

Kvist S, Min GS, Siddall ME. Diversity and selective pressures of anticoagulants in three medicinal leeches (Hirudinida: Hirudinidae, Macrobdellidae). Ecol Evol. 2013;3(4):918-33.

Min GS, Sarkar IN, Siddall ME. Salivary transcriptome of the North American medicinal leech, Macrobdella decora. J Parasitol. 2010;96(6):1211-21.

Large-scale venom-based drug discovery

Escoubas P, King GF. Venomics as a drug discovery platform. Expert Rev Proteomics. 2009;6(3):221-4.

Palagi A, Koh JM, Leblanc M, et al. Unravelling the complex venom landscapes of lethal Australian funnel-web spiders (Hexathelidae: Atracinae) using LC-MALDI-TOF mass spectrometry. J Proteomics. 2013;80:292-310.

VENOMICS
The official website of the EU VENOMICS project.

Organizers

Mandë Holford, PhD

Hunter College, CUNY; American Museum of Natural History
website | publications

Mandë Holford is as an assistant professor of chemistry at Hunter College and CUNY Graduate Center with a scientific appointment at the American Museum of Natural History. Her dual appointment reflects her interdisciplinary research, which combines chemistry and biology to discover, characterize, and deliver novel neuropeptides from venomous marine snails (cone snails, terebrids, and turrids) as tools for manipulating cell signaling in the nervous system. She has received funds from the National Science Foundation (NSF), the National Institutes of Health (NIH), and the Alfred P. Sloan Foundation to support her independent research. Holford received her PhD in synthetic protein chemistry from The Rockefeller University. She was recently award the prestigious Camille Dreyfus Teacher-Scholar Award and, in 2011, received an NSF CAREER Award.

Steven Gross, PhD

Weill Cornell Medical College
website | publications

Steven Gross is a professor of pharmacology, director of the Mass Spectrometry Core Facility, and director of advanced training in pharmacology at the Weill Cornell Medical College. Gross received an award from the American Chemical Society for Achievements in Mass Spectrometry in 2011. His primary research interest is in cell–cell communication, with a focus on nitric oxide (NO) and reactive molecules as mediators of cell signaling. In the 1980s, Gross and colleagues made the initial identification of L-arginine as the precursor of NO in blood vessels. They were also first to establish that NOS inhibition elevates blood pressure in animals, demonstrating that NO plays a physiological role in controlling blood pressure and vascular tone. Research efforts have since been directed toward understanding NO synthesis in cells. His studies led to core technologies for the creation of ArgiNOx Inc., a biotech start-up that seeks to develop novel NO-based drugs. Gross's research is supported in part by a MERIT Award from the National Heart, Lung and Blood Institute, NIH. He is a founder and board director of the Nitric Oxide Society and chairs the Steering Committee of the Biochemical Pharmacology Discussion Group (BPDG) at the Academy. Gross received his PhD in biomedical science from the Mount Sinai School of Medicine.

Jennifer Henry, PhD

The New York Academy of Sciences

Jennifer Henry is the director of Life Sciences at the New York Academy of Sciences. Henry joined the Academy in 2009, before which she was a publishing manager in the Academic Journals division at Nature Publishing Group. She also has eight years of direct editorial experience as editor of Functional Plant Biology for CSIRO Publishing in Australia. She received her PhD in plant molecular biology from the University of Melbourne, specializing in the genetic engineering of transgenic crops. As director of Life Sciences, she is responsible for developing scientific symposia across a range of life sciences, including biochemical pharmacology, neuroscience, systems biology, genome integrity, infectious diseases and microbiology. She also generates alliances with organizations interested in developing programmatic content.


Keynote Speaker

Baldomero M. Olivera, PhD

University of Utah
website | publications

Baldomero ("Toto") Olivera holds a PhD in the biophysical chemistry of DNA from California Institute of Technology and completed postdoctoral work in biochemistry at Stanford University. He held a faculty position at the University of the Philippines Medical School before moving to the University of Utah, where he is a distinguished professor of biology. His early research included the discovery and biochemical characterization of E. coli DNA ligase, which made the recombinant DNA revolution in biology possible. Olivera studies biologically active peptides found in the venoms of predatory cone snails, which include many peptide neurotoxins ("conopeptides"). Conus venom components are used to investigate the molecular components of nervous systems, particularly ion channels. The cone snail project has led to research into topics from protein folding and post-translational modification to gene organization and speciation. Several peptides discovered in Olivera's lab have been developed as therapeutic drugs. Three have reached human clinical trials and one (Prialt) has been approved by the FDA for the treatment of intractable pain. Additional applications of these compounds as therapeutics for heart attack, stroke, epilepsy, and other neuropathologies are being explored.


Speakers

Anirban Banerjee, PhD

National Institute of Child Health and Human Development, NIH
website | publications

Anirban Banerjee holds an MSc in chemistry from the Indian Institute of Technology. As a PhD student in Dr. Greg Verdine's lab at Harvard University, he combined tools and techniques from synthetic oligonucleotide chemistry, biochemistry, and crystallography to study how a particular class of DNA repair proteins locate rare sites of damaged bases in DNA and discriminate between undamaged and damaged DNA. In his postdoctoral studies in the lab of Dr. Rod MacKinnon at The Rockefeller University, he focused on voltage-dependent K+ channels (Kv channels), including the mechanism by which small peptide toxins from the venom of poisonous animals target these ion channels. In 2012 he became an Earl Stadtman Investigator in the Cell Biology and Metabolism Program at the Eunice Kennedy Shriver National Institute of Child Health and Development, NIH. He is the recipient of the ACS Nobel Laureate Signature Award in graduate education, a postdoctoral fellowship from the Damon Runyon Cancer Research Foundation, and the NIH Director's Challenge Award.

Carole A. Bewley, PhD

National Institute of Diabetes and Digestive and Kidney Diseases, NIH
website | publications

Carole A. Bewley received her PhD from Scripps Institution of Oceanography in marine natural products chemistry/oceanography and completed postdoctoral research in the Laboratory of Chemical Physics at the NIH. She joined the faculty of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, where she is a senior investigator and chief of the Natural Products Chemistry Section and deputy chief of the Laboratory of Bioorganic Chemistry. She leads a multidisciplinary research program that focuses on discovery and structural studies of natural products and protein inhibitors that have therapeutic potential in antibiotics and viral entry inhibitors. She has received the NIH Director's Award and the Paul Dowd Lectureship and is an inventor on patents for discoveries in anti-infectives.

Pierre Escoubas, PhD

VenomeTech
website | publications

Pierre Escoubas is president and CEO of VenomeTech, a biotechnology startup company in the Sophia-Antipolis French research cluster. Escoubas obtained his PhD in chemical entomology at the University Pierre and Marie Curie, France, and worked as a postdoctoral associate at the University of Georgia before moving to Japan as a research associate for the Japan Research and Development Corporation. He later joined the Suntory Institute for Bioorganic Research (SUNBOR), Japan, to work on peptide toxins from animal venoms, and then returned to France to join Prof. M. Lazdunski at the CNRS Institute of Molecular and Cellular Pharmacology and as an associate professor at the University of Paris and the University of Nice Sophia Antipolis. He founded VenomeTech in 2009 and has since been leading the company toward the development of innovative drugs from animal venom peptides. Escoubas is leading the FP7 European project VENOMICS, a large-scale endeavor to develop novel drugs from animal venom peptides. His research interests include the discovery of novel peptide toxins from venomous animals, biological mass spectrometry, peptide engineering and folding, ion channel molecular pharmacology, and the development of novel peptide therapeutics.

Bryan Fry, PhD

The University of Queensland, Australia
website | publications

Bryan G. Fry holds a PhD from the University of Queensland, Australia, where he is now an associate professor. He has published widely on venomous animals including cephalopods, centipedes, jellyfish, reptiles, scorpions, spiders, slow lorises, and even vampire bats. His fieldwork has taken him to all the continents, working on projects including collecting venomous octopuses in Antarctica. His discoveries include the finding that the iconic Komodo Dragon is venomous. His research has led to the discovery of compounds that are useful as medicines, and he has, for example, patented taipan snake venom peptides for use in treating congestive heart failure.

Inés Ibañez-Tallon, PhD

The Rockefeller University
website | publications

Inés Ibañez-Tallon is a visiting associate professor at The Rockefeller University and group leader at the Max Delbruck Center for Molecular Medicine, Germany. She studied biology at the University of Barcelona, Spain, obtained her PhD in genetic sciences from the University of Milan, Italy, and completed postdoctoral studies at The Rockefeller University.

Mark E. Siddall, PhD

American Museum of Natural History
website | publications

Mark E. Siddall is curator of the Division of Invertebrate Zoology at the American Museum of Natural History. His research has focused on the evolutionary biology of parasites from single-celled microbes to leeches. Siddall is now researching Darwinian selection and the diversity of hemotoxic venom proteins of leeches such as Tyranobdella rex (T. rex), recently described from the Amazon. Siddall has led field expeditions for the American Museum of Natural History. He is a professor in the museum's Richard Gilder Graduate School and is a principal investigator in its Sackler Institute for Comparative Genomics. In addition to serving as vice president of the American Society of Parasitologists, Siddall is also the curator of the museum's Picturing Science: Museum Scientists and Imaging Technologies exhibition and co-curator of the Irma and Paul Milstein Family Hall of Ocean Life and the Power of Poison exhibition. He received his PhD in zoology from the University of Toronto, Canada.

Beatrix Ueberheide, PhD

NYU Langone Medical Center
website | publications

Beatrix Ueberheide joined the faculty of New York University as an assistant professor in the Department of Biochemistry and Molecular Pharmacology and as director of the Proteomics Core. She has experience in biological mass spectrometry, especially method development, mapping of post-translational modifications, de novo sequencing, and "Bottom Up" and "Top Down" strategies, as well as comprehensive protein characterization in complex mixtures. Ueberheide contributed to studies ranging from analyzing chromatin to characterizing venoms and sequencing complex antibody mixtures. She received her PhD in chemistry at the University of Virginia in the lab of Dr. Donald Hunt, where she focused on histone post-translational modifications. She completed postdoctoral training with Dr. Brian Chait at The Rockefeller University, where she developed de novo sequencing strategies for analysis of venom components and established techniques to study antibodies isolated from HIV-infected long-term non-progressors. She is currently working to develop advanced mass-spectrometric techniques for the characterization, de novo sequencing, and quantitation of proteins and their post-translational modifications.


Panelists

Yvonne M. Angell, PhD

Ipsen

Yvonne M. Angell is director of chemistry at Ipsen. She earned a PhD in medicinal chemistry at the University of Wisconsin–Madison and completed postdoctoral work at the University of Minnesota. Angell has 15 years of experience in the pharmaceutical industry, including design of novel, constrained peptide libraries to inhibit protein–protein interactions at Eli Lilly and Co.; design and development of bead-based binding assays to identify new hits aimed at inhibiting protein–protein interactions at Genetics Institute (now Pfizer); and hit-to-lead optimization on several peptide therapeutic projects as a senior scientist at Affymax. Her current work at Ipsen is focused on discovery, design, and engineering of novel, potent, selective lead-peptide and peptide chimeric compounds for oncology and endocrinology targets. She has led several cross-functional project teams from early discovery through preclinical development.

Les P. Miranda, PhD

Amgen

Les P. Miranda is director of research in therapeutic discovery at Amgen Inc. He obtained his PhD in synthetic peptide and protein chemistry from the University of Queensland, Australia. Miranda held a research position at the Carlsberg Laboratory, Denmark, and then served as an associate director at Gryphon Therapeutics, where he contributed to the development of methods for the total chemical synthesis and medicinal optimization of protein therapeutics. At Amgen, he is responsible for peptide and related hybrid discovery, and he has supported preclinical and early development programs. Miranda has led several cross-functional teams through drug discovery and development.

Hazel H. Szeto, MD, PhD

Stealth Peptides Inc.

Hazel H. Szeto is a professor of pharmacology at Weill Cornell Medical College and director of the Research Program in Mitochondrial Therapeutics. Szeto has extensive expertise in peptide-based drug design, pharmacokinetics, and preclinical drug development. She has developed several highly potent and selective opioid peptide analogs that are metabolically stable and can readily cross the blood–brain barrier. In 2004, Szeto discovered that certain cell-permeable aromatic-cationic tetrapeptides selectively target and concentrate in the inner mitochondrial membrane. She has evaluated their efficacy in protecting and restoring mitochondrial bioenergetics in preclinical models of age-associated complex diseases, including cardiorenal diseases, metabolic diseases, neurodegenerative diseases, skeletal muscle weakness, and chronic pain. She founded Stealth Peptides International to take these "first-in-class" cardiolipin therapeutics from bench to bedside. The first drug candidate (Bendavia) is in phase II clinical trials for acute cardiorenal ischemic injury and heart failure. Szeto is a full-time faculty member at Weill Cornell Medical College and a scientific consultant for Stealth Peptides. She received her MD and PhD in pharmacology from Cornell University Medical College.

Nicholette Zeliadt

Nicholette Zeliadt writes about science for scientists and non-scientists alike. She has a background in biochemistry and nutrition, and a PhD in environmental health sciences from the University of Minnesota. In pursuit of science, she has traveled by ship to the South Pacific Gyre, traversed the Willamette Valley by bike, and encountered 12 of the planet's 13 climatic zones. She has written for Scientific American, Proceedings of the National Academy of Sciences, BioTechniques, and About.com.

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