Cone Snails: a Big Store of Conotoxins for Novel Drug Discovery
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toxins Review Cone Snails: A Big Store of Conotoxins for Novel Drug Discovery Bingmiao Gao 1,†, Chao Peng 2,†, Jiaan Yang 3, Yunhai Yi 2,4 ID , Junqing Zhang 1,* and Qiong Shi 2,4,* 1 Hainan Provincial Key Laboratory of Research and Development of Tropical Medicinal Plants, Hainan Medical University, Haikou 571199, China; [email protected] or [email protected] 2 Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China; [email protected] (C.P.); [email protected] (Y.Y.) 3 Micro Pharmtech, Ltd., Wuhan 430075, China; [email protected] 4 BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China * Correspondence: [email protected] or [email protected] (J.Z.); [email protected] (Q.S.); Tel.: +86-898-6689-5337 (J.Z.); +86-755-3630-7807 (Q.S.) † These authors contributed equally to this work. Academic Editor: Steve Peigneur Received: 26 October 2017; Accepted: 4 December 2017; Published: 7 December 2017 Abstract: Marine drugs have developed rapidly in recent decades. Cone snails, a group of more than 700 species, have always been one of the focuses for new drug discovery. These venomous snails capture prey using a diverse array of unique bioactive neurotoxins, usually named as conotoxins or conopeptides. These conotoxins have proven to be valuable pharmacological probes and potential drugs due to their high specificity and affinity to ion channels, receptors, and transporters in the nervous systems of target prey and humans. Several research groups, including ours, have examined the venom gland of cone snails using a combination of transcriptomic and proteomic sequencing, and revealed the existence of hundreds of conotoxin transcripts and thousands of conopeptides in each Conus species. Over 2000 nucleotide and 8000 peptide sequences of conotoxins have been published, and the number is still increasing quickly. However, more than 98% of these sequences still lack 3D structural and functional information. With the rapid development of genomics and bioinformatics in recent years, functional predictions and investigations on conotoxins are making great progress in promoting the discovery of novel drugs. For example, !-MVIIA was approved by the U.S. Food and Drug Administration in 2004 to treat chronic pain, and nine more conotoxins are at various stages of preclinical or clinical evaluation. In short, the genus Conus, the big family of cone snails, has become an important genetic resource for conotoxin identification and drug development. Keywords: conotoxin; cone snail; transcriptome; proteome; drug development 1. Introduction Forming the biggest single genera of living marine invertebrates [1], cone snails are composed of various carnivorous predators. They are usually classified into three groups depending on their feeding habits: worm hunters (vermivorous), mollusk hunters (molluscivorous), and fish hunters (piscivorous) [1–3]. There are now around 700 Conus species, with the majority distributed throughout tropical and subtropical waters, such as the South China Sea, Australia, and the Pacific Ocean [4]. The venom gland of cone snails can secrete large amounts of unique neurotoxic peptides, commonly referred to as conopeptides or conotoxins, and most conotoxins are rich in disulfide bridges with many pharmacological activities [5,6]. Each Conus species typically possesses an average of 100–200 conotoxins as potential pharmacological targets [7]. More than 80,000 natural conotoxins Toxins 2017, 9, 397; doi:10.3390/toxins9120397 www.mdpi.com/journal/toxins Toxins 2017, 9, 397 2 of 17 Toxins 2017, 9, 397 2 of 18 average of 100–200 conotoxins as potential pharmacological targets [7]. More than 80,000 natural conotoxins have been estimated to exist in various cone snails around the world [7–9]. Therefore, have been estimated to exist in various cone snails around the world [7–9]. Therefore, the cone snails the cone snails construct the largest library of natural drug candidates for the development of construct the largest library of natural drug candidates for the development of marine drugs. marine drugs. Usually, conotoxins are categorized into many different families based on the types of their Usually, conotoxins are categorized into many different families based on the types of their molecularmolecular targets targets and and corresponding corresponding pharmacological pharmacological activities activities [9,10 ].[9,10]. Their structuresTheir structures and functions and arefunctions highly diverseare highly and diverse mainly and target mainly membrane target membrane proteins, particularly proteins, particularly ion channels, ion membranechannels, receptors,membrane and receptors, transporters. and transporte Some toxinsrs. thatSome have toxins specific that targetshave specific and short targets sequences and short and sequences are easy to synthesizeand are easy have to been synthesize developed have as drugbeen leadsdeveloped and effective as drug research leads and agents effective for distinguishing research agents subtypes for ofdistinguishing molecular targets subtypes [10,11 of]. molecular The most targets well-known [10,11]. commercial The most well-known conotoxin iscommercial!-MVIIA conotoxin (ziconotide), is whichω-MVIIA hasbeen (ziconotide), derived fromwhich the has venom been derived of a fish-hunting from the venomC. magus of species,a fish-hunting and approved C. magus by species, the U.S. Foodand andapproved Drug Administrationby the U.S. Food (FDA) and toDrug treat Administ chronic painration in (FDA) serious to cancer treat andchronic AIDS pain patients in serious [12,13 ]. Conotoxinscancer and areAIDS now patients increasingly [12,13]. Conotoxins undergoing are development now increasingly for the undergoing treatment development of multiple diseasesfor the includingtreatment pain, of multiple Alzheimer’s diseases disease, including Parkinson’s pain, disease, Alzheimer’s cardiac disease, infarction, Parkinson’s hypertension, disease, and cardiac various neurologicalinfarction, hypertension, diseases [14– 16and]. Therefore,various neurological conotoxins, diseases being important [14–16]. Therefore, potential therapeuticconotoxins, targetsbeing dueimportant to the physiological potential therapeutic roles that targets they due play, to are the a ph practicalysiological prospect roles that with they wide play, implications are a practical in the neuroscienceprospect with research wide implications field. in the neuroscience research field. 2.2. Diversity Diversity of of Cone Cone Snails Snails 2.1.2.1. Various Various Phenotypes Phenotypes ConeCone snails snails havehave beenbeen ofof interestinterest asas collector’scollector’s items for for a a long long time time due due to to their their beautiful beautiful patternedpatterned shells shells (Figure (Figure1), and1), theand identification the identification of Conus of speciesConus isspecies mainly is based mainly on theirbased morphology on their andmorphology color of shell. and color The of genus shell.Conus The genusis a memberConus is a of member the most of diversethe most and diverse taxonomically and taxonomically complex superfamily,complex superfamily, Conoidea. Conoidea. According According to recent estimations, to recent estimations, it includes it around includes 700 around species, 700 and species, most of themand stillmost remain of them undescribed still remain [undescribed17]. However, [17]. species However, determination species determination of live cone of snails live cone using snails shell characteristicsusing shell characteristics poses difficulties poses due difficulties to regional due andto regional intra-specific and intra-specific variations [variations18]. [18]. FigureFigure 1.1.Twenty Twenty mostmost abundantabundant Conus species in in the the South South China China Sea. Sea. TheThe rapid rapid development development of of molecular molecular biology, biology, the the application application of of the the mitochondrial mitochondrial genome, genome, and and the partialthe partial sequences sequences of COI of (cytochromeCOI (cytochrome c oxidase c oxidas subunite subunit I), 16S I), rRNA, 16S rRNA, 12S rRNA, 12S rRNA, and calmodulinand calmodulin genes havegenes all have enabled all enabled a greater a greater understanding understanding of the of diversity the diversity of gastropods of gastropods at various at various levels, levels, in terms in ofterms population, of population, varieties, varieties, species, species, and so onand [19 so–25 on]. Until[19–25]. recently, Until recently, efforts on efforts molecular on molecular taxonomy havetaxonomy been focused have been on the focused higher on taxonomic the higher categories taxonomic above categories the species above level. the A species phylogenetic level. treeA ofphylogenetic 72–138 Conus treespecies of 72–138 with known Conus diets species was obtainedwith known on the diets basis was ofmitochondrial obtained on 16Sthe rRNAbasis andof nuclearmitochondrial calmodulin 16S rRNA gene sequences,and nuclear and calmodulin a distinctive gene clustering sequences, of and species a distinctive with similar clustering diets wasof observedspecies [with26,27 ].similar More detailsdiets was on a phylogeneticobserved [26,27]. basis More were establisheddetails on [28a ]phylogenetic to evaluate morphological basis were Toxins 2017, 9, 397 3 of 18 Toxins 2017, 9, 397 3 of 17 criteria and characterize