Stingray Venom Proteins : Mechanisms of Action Revealed Using a Novel Network Pharmacology Approach

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2022
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Kirchhoff, Kim N.
Billion, André
Kremb, Stephan
Wilke, Thomas
Vilcinskas, Andreas
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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.

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570 Biowissenschaften, Biologie
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transcriptomics; high-content screening; multi-omics data integration; drug discovery; venomics
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ISO 690KIRCHHOFF, Kim N., André BILLION, Christian R. VOOLSTRA, Stephan KREMB, Thomas WILKE, Andreas VILCINSKAS, 2022. Stingray Venom Proteins : Mechanisms of Action Revealed Using a Novel Network Pharmacology Approach. In: Marine Drugs. MDPI. 2022, 20(1), 27. eISSN 1660-3397. Available under: doi: 10.3390/md20010027
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@article{Kirchhoff2022-01Sting-56077,
  year={2022},
  doi={10.3390/md20010027},
  title={Stingray Venom Proteins : Mechanisms of Action Revealed Using a Novel Network Pharmacology Approach},
  number={1},
  volume={20},
  journal={Marine Drugs},
  author={Kirchhoff, Kim N. and Billion, André and Voolstra, Christian R. and Kremb, Stephan and Wilke, Thomas and Vilcinskas, Andreas},
  note={Article Number: 27}
}
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