Abstract
Animal venoms offer a valuable source of potent new drug leads, but their mechanisms of action are largely unknown. We therefore developed a novel network pharmacology approach based on multi-omics functional data integration to predict how stingray venom disrupts the physiological systems of target animals. We integrated 10 million transcripts from five stingray venom transcriptomes and 848,640 records from three high-content venom bioactivity datasets into a large functional data network. The network featured 216 signaling pathways, 29 of which were shared and targeted by 70 transcripts and 70 bioactivity hits. The network revealed clusters for single envenomation outcomes, such as pain, cardiotoxicity and hemorrhage. We carried out a detailed analysis of the pain cluster representing a primary envenomation symptom, revealing bibrotoxin and cholecystotoxin-like transcripts encoding pain-inducing candidate proteins in stingray venom. The cluster also suggested that such pain-inducing toxins primarily activate the inositol-3-phosphate receptor cascade, inducing intracellular calcium release. We also found strong evidence for synergistic activity among these candidates, with nerve growth factors cooperating with the most abundant translationally-controlled tumor proteins to activate pain signaling pathways. Our network pharmacology approach, here applied to stingray venom, can be used as a template for drug discovery in neglected venomous species.
Highlights
More than 200,000 animal species produce venom, mostly for defense and/or predation [1,2,3,4]
RNA was isolated from five stingray species representing the two most important stingray habitats and the two largest families: Dasyatidae and Potamotrygonidae
The bioinformatics workflow is shown in Appendix A (Figure A1), the complete datasets are provided in Datasets S1–S5, quality parameters are listed in Table A1, and the evaluation is summarized in Dataset S9
Summary
More than 200,000 animal species produce venom, mostly for defense and/or predation [1,2,3,4]. Venoms are cocktails of up to 3000 bioactive compounds, including protein/peptide toxins, metabolites and salts [3,5]. Venoms are produced in specialized tissues or glands, and are actively transferred to target organisms via spines, teeth or modified cell-harpoons [3]. Venom targets are found in most major physiological pathways, inducing local effects such as tissue disruption and systemic effects such as paralysis [3,6,7,8]. The diverse components of venoms offer a rich source of novel molecular entities for medical applications. The first example was the cardiovascular agent captopril, which was approved in 1981 for the treatment of hypertension and congestive heart failure [9]
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