toxins Communication Phylogeny-Guided Selection of Priority Groups for Venom Bioprospecting: Harvesting Toxin Sequences in Tarantulas as a Case Study Tim Lüddecke 1,*, Andreas Vilcinskas 1,2,3 and Sarah Lemke 2 1 Department of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology, Winchesterstr. 2, 35394 Gießen, Germany 2 Institute for Insect Biotechnology, Justus-Liebig-University of Gießen, Heinrich-Buff-Ring 26-32, 35392 Gießen, Germany 3 LOEWE Centre for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt, Germany * Correspondence: [email protected] Received: 19 July 2019; Accepted: 22 August 2019; Published: 25 August 2019 Abstract: Animal venoms are promising sources of novel drug leads, but their translational potential is hampered by the low success rate of earlier biodiscovery programs, in part reflecting the narrow selection of targets for investigation. To increase the number of lead candidates, here we discuss a phylogeny-guided approach for the rational selection of venomous taxa, using tarantulas (family Theraphosidae) as a case study. We found that previous biodiscovery programs have prioritized the three subfamilies Ornithoctoninae, Selenocosmiinae, and Theraphosinae, which provide almost all of the toxin sequences currently available in public databases. The remaining subfamilies are poorly represented, if at all. These overlooked subfamilies include several that form entire clades of the theraphosid life tree, such as the subfamilies Eumenophorinae, Harpactirinae, and Stromatopelminae, indicating that biodiversity space has not been covered effectively for venom biodiscovery in Theraphosidae. Focusing on these underrepresented taxa will increase the likelihood that promising candidates with novel structures and mechanisms of action can be identified in future bioprospecting programs. Keywords: spiders; Theraphosidae; phylogenetics; venomics; bioprospecting; taxonomic bias Key Contribution: Research on tarantula venom focuses only on a small fraction of the overall biodiversity. By combining phylogenetic and venomic data, we herein highlight the key tarantula lineages that need to be studied for optimizing bioprospecting within the family. This approach might contribute to streamline and economized venom biodiscovery from diverse animal groups in the future. 1. Introduction Nature abounds with bioactive molecules synthesized by species that interact with each other, either competitively or cooperatively. These species have evolved the ability to produce chemical components that increase their fitness and favor their survival, for example by antagonizing competitors, predators, prey, and pathogens or by attracting symbionts and commensals. In the search for drugs against infectious and acquired diseases, humans have often turned to such natural bioactive molecules because they have acquired outstanding pharmacologies through millions of years of subsequent evolutive optimization towards potent bioactivity for their natural function. Accordingly, many of our current drugs are natural chemical entities or their derivatives [1]. Toxins 2019, 11, 488; doi:10.3390/toxins11090488 www.mdpi.com/journal/toxins Toxins 2019, 11, 488 2 of 10 ToxinsBioactive 2019, 11, x molecules FOR PEER REVIEW are often sourced from microbes and plants, but attention has2 turnedof 10 more recently to animal venoms. These evolved for hunting prey, defense against predation, and Bioactive molecules are often sourced from microbes and plants, but attention has turned more intraspecific competition [2]. The in-depth survey of venoms and their components has already recently to animal venoms. These evolved for hunting prey, defense against predation, and led to the development of several important drugs, such as the analgesic ziconotide from the cone intraspecific competition [2]. The in-depth survey of venoms and their components has already led snail Conus magus, the antidiabetic exenatide, a synthetic derivative of exendin-4 from venom of to the development of several important drugs, such as the analgesic ziconotide from the cone snail the beaded-lizard Heloderma suspectum, and the antihypertensive captopril from the lancehead viper Conus magus, the antidiabetic exenatide, a synthetic derivative of exendin-4 from venom of the Bothropsbeaded-lizard jararaca Heloderma[3]. That suspectum said, all, and venom-derived the antihypertensive drugs have captopril been from isolated the fromlancehead a small viper and unrepresentativeBothrops jararaca minority [3]. That of said, venomous all venom-derived species, in particular drugs have from been the isolated largest andfrom most a small dangerous and taxa.unrepresentative However, venom minority evolved of veno convergentlymous species, in metazoans in particular multiple from the times largest [2]. and Several most of dangerous the lineages thattaxa. successfully However, evolvedvenom evolved venom convergently systems are additionallyin metazoans quite multiple diverse times on [2]. the Several species of levelthe lineages with fish, insects,that successfully or arachnids evolved being venom some examples.systems are Interestingly, additionally quite most diverse representatives on the species of these level groups with fish, have notinsects, yet been or arachnids studied for being their some venom examples. in more Interestingly, detail. 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[5], There but the overwhelmingare currently majority48,249 recognized of species species that have of spiders, been investigated almost all of in which the search produce for venom-derived venom [5], but drugsthe areoverwhelming again either themajority larger of or species more that dangerous have been members investigated (Figure in the1), especiallysearch for venom-derived from the genera drugsAtrax , Hadronycheare again, eitherMissulena the larger, Sicarius or more, Latrodectus dangerous, Hexophtalma members ,(Figure and Phoneutria 1), especially. This from phenomenon the genera hasAtrax been, coinedHadronyche as “taxonomic, Missulena bias”, Sicarius and, wasLatrodectus subject, Hexophtalma to critical discussion, and Phoneutria in the. recentThis phenomenon past [6]. has been coined as “taxonomic bias” and was subject to critical discussion in the recent past [6]. FigureFigure 1. 1.Taxonomic Taxonomic bias bias in in spider spider venomvenom research. Given Given in in (A (A) )are are spider spider families families which which have have been been studiedstudied for for their their venom venom so so far, far, together together withwith anan assignmentassignment of of threat threat potential potential and and size. size. Brackets Brackets indicateindicate that that only only a a small small fraction fraction ofof includedincluded speciesspecies are are either either dangerous dangerous or or large. large. Further Further note note that that thethe grouping grouping “other” “other” in in reality reality represents represents the the remaining remaining 109 109 spider spider families, families, thus thus “other” “other” contains contains the majoritythe majority of spider of spider biodiversity. biodiversity. 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