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Conotoxins: Chemistry and Biology

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Conotoxins: Chemistry and Biology Conotoxins: Chemistry and Biology Ai-Hua Jin1*, Markus Muttenthaler*1,2, Sebastien Dutertre3, Himaya Siddhihalu Wickrama Hewage1, Quentin Kaas1, David J Craik1**, Richard J Lewis1** and Paul F Alewood1** 1 Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia 2Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria. 3 Institut des Biomolécules Max Mousseron, Département des acides amines, Peptides et Protéines, Unité Mixte de Recherche 5247, Université Montpellier 2 – Centre Nationale de la Recherche Scientifique, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France Corresponding authors: ** Professor P F Alewood, E-mail: [email protected] **Professor D Craik, E-mail: [email protected] **Professor R J Lewis, E-mail: [email protected] * Contributed equally to this manuscript ** Corresponding authors 1 Abstract The venom of the marine predatory cone snails (genus Conus) has evolved for prey capture and defense, providing the basis for survival and rapid diversification of the now estimated 750+ species. A typical Conus venom contains hundreds to thousands of bioactive peptides known as conotoxins. These mostly disulfide-rich and well-structured peptides act on a wide range of targets such as ion channels, G protein-coupled receptors, transporters and enzymes. Conotoxins are of interest to neuroscientists as well as drug developers due to their exquisite potency and selectivity, not just against prey but also mammalian targets, thereby providing a rich source of molecular probes and therapeutic leads. The rise of integrated venomics has accelerated conotoxin discovery with now well over 10,000 conotoxin sequences published. However, their structural and pharmacological characterization lags considerably behind. In this review, we highlight the diversity of new conotoxins uncovered since 2014, their three-dimensional structures and folds, novel chemical approaches to their syntheses, and their value as pharmacological tools to unravel complex biology. Additionally, we discuss challenges and future directions for the field. 2 Table of Contents 1. Introduction .......................................................................................................................................... 87 2. Conotoxin classification and nomenclature ......................................................................................... 98 3. Integrated venomics ......................................................................................................................... 1211 3.1 Transcriptomics. ............................................................................................................................ 1211 3.2 Proteomics ..................................................................................................................................... 1615 3.3 Bioinformatics tools ....................................................................................................................... 1716 3.4 New sequences ............................................................................................................................... 1817 4. Structural diversity ........................................................................................................................... 3433 4.1 Structures of frameworks with four cysteines ............................................................................... 4342 4.2 Structures of Frameworks with six cysteines ................................................................................ 5049 4.3 Large peptides forming dimers ...................................................................................................... 5251 4.4 Disulfide-poor conotoxins ............................................................................................................. 5352 5. Conotoxin Synthesis ........................................................................................................................ 5453 5.1 Oxidative folding strategies ........................................................................................................... 5554 5.2 Directed folding strategies ............................................................................................................. 5655 5.3 Disulfide bond isosteres / peptide mimetics .................................................................................. 6160 5.4 Cyclic conotoxins .......................................................................................................................... 6362 5.5 Multivalent conotoxins .................................................................................................................. 6463 6. Pharmacological diversity ............................................................................................................... 6665 3 6.1 Novel conotoxins acting on ion channels and transporters ........................................................... 6665 6.1.1. Calcium channel modulators ................................................................................................. 6665 6.1.2 Calcium channel modulation via GABAB receptor ................................................................ 6867 6.2 Novel conotoxins acting on nicotinic acetylcholine receptors ...................................................... 7069 6.2.1 nAChR modulators ................................................................................................................. 7069 6.2.2 Atypical α-conotoxins targeting nAChRs ............................................................................. 7170 6.3 Sodium channel modulators .......................................................................................................... 7473 6.4 Potassium channel modulators ...................................................................................................... 7776 6.5 Activities beyond voltage- and ligand-gated ion channels ............................................................ 7877 6.5.1 Conoinsulins ........................................................................................................................... 7977 6.5.2 RF-amide peptides .................................................................................................................. 8079 6.5.3 Granulin-like conotoxins ........................................................................................................ 8281 7. Concluding remarks and outlook ..................................................................................................... 8483 8 References ........................................................................................................................................ 8685 4 List of Figures Figure 1: Distribution pattern of the frameworks.. .................................................................................. 1110 Figure 2: Alignment of selected framework I conotoxins. ...................................................................... 1918 Figure 3: Alignment of selected framework II conotoxins. ..................................................................... 1918 Figure 4: Alignment of selected framework III conotoxins. ................................................................... 2019 Figure 5: Alignment of selected framework IV conotoxins. ................................................................... 2120 Figure 6: Alignment of selected framework V conotoxins. .................................................................... 2120 Figure 7: Alignment of selected framework VI/VII conotoxins. ............................................................ 2221 Figure 8: Alignment of selected framework VIII conotoxins. ............................................................... 2322 Figure 9: Alignment of selected framework IX conotoxins ........................................................................ 23 Figure 10: Alignment of selected framework X conotoxins. .................................................................. 2423 Figure 11: Alignment of selected framework XI conotoxins .................................................................. 2524 Figure 12: Alignment of selected framework XII conotoxins ................................................................. 2625 Figure 13: Alignment of selected framework XIII conotoxins. .............................................................. 2625 Figure 14: Alignment of selected framework XIV conotoxins. .............................................................. 2726 Figure 15: Alignment of selected framework XV conotoxins ................................................................. 2726 Figure 16: Alignment of selected framework XVI conotoxins ............................................................... 2827 Figure 17: Alignment of selected framework XVII conotoxins .............................................................. 2827 Figure 18: Alignment of selected framework XVIII conotoxins ............................................................. 2928 Figure 19: Alignment of framework XIX conotoxins. ............................................................................ 2928 Figure 20: Alignment of selected framework XX conotoxins ................................................................. 3029 Figure 21: Alignment of selected framework XXI conotoxins. .............................................................
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