Stingray Venom Proteins: Mechanisms of Action Revealed Using a Novel Network Pharmacology Approach
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...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-12-01
|
| Series: | Marine Drugs |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1660-3397/20/1/27 |
| _version_ | 1797492552035729408 |
|---|---|
| author | Kim N. Kirchhoff André Billion Christian R. Voolstra Stephan Kremb Thomas Wilke Andreas Vilcinskas |
| author_facet | Kim N. Kirchhoff André Billion Christian R. Voolstra Stephan Kremb Thomas Wilke Andreas Vilcinskas |
| author_sort | Kim N. Kirchhoff |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T01:05:19Z |
| format | Article |
| id | doaj.art-516bde2f5b224f3fb204e67f17a2bde3 |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-03-10T01:05:19Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-516bde2f5b224f3fb204e67f17a2bde32023-11-23T14:27:38ZengMDPI AGMarine Drugs1660-33972021-12-012012710.3390/md20010027Stingray Venom Proteins: Mechanisms of Action Revealed Using a Novel Network Pharmacology ApproachKim N. Kirchhoff0André Billion1Christian R. Voolstra2Stephan Kremb3Thomas Wilke4Andreas Vilcinskas5Department of Animal Ecology and Systematics, Justus Liebig University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, GermanyDepartment of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology, Ohlebergsweg 12, 35392 Giessen, GermanyDepartment of Biology, University of Konstanz, 78457 Konstanz, GermanyRed Sea Research Center, Division of Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi ArabiaDepartment of Animal Ecology and Systematics, Justus Liebig University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, GermanyDepartment of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology, Ohlebergsweg 12, 35392 Giessen, GermanyAnimal 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.https://www.mdpi.com/1660-3397/20/1/27transcriptomicshigh-content screeningmulti-omics data integrationdrug discoveryvenomics |
| spellingShingle | Kim N. Kirchhoff André Billion Christian R. Voolstra Stephan Kremb Thomas Wilke Andreas Vilcinskas Stingray Venom Proteins: Mechanisms of Action Revealed Using a Novel Network Pharmacology Approach Marine Drugs transcriptomics high-content screening multi-omics data integration drug discovery venomics |
| title | Stingray Venom Proteins: Mechanisms of Action Revealed Using a Novel Network Pharmacology Approach |
| title_full | Stingray Venom Proteins: Mechanisms of Action Revealed Using a Novel Network Pharmacology Approach |
| title_fullStr | Stingray Venom Proteins: Mechanisms of Action Revealed Using a Novel Network Pharmacology Approach |
| title_full_unstemmed | Stingray Venom Proteins: Mechanisms of Action Revealed Using a Novel Network Pharmacology Approach |
| title_short | Stingray Venom Proteins: Mechanisms of Action Revealed Using a Novel Network Pharmacology Approach |
| title_sort | stingray venom proteins mechanisms of action revealed using a novel network pharmacology approach |
| topic | transcriptomics high-content screening multi-omics data integration drug discovery venomics |
| url | https://www.mdpi.com/1660-3397/20/1/27 |
| work_keys_str_mv | AT kimnkirchhoff stingrayvenomproteinsmechanismsofactionrevealedusinganovelnetworkpharmacologyapproach AT andrebillion stingrayvenomproteinsmechanismsofactionrevealedusinganovelnetworkpharmacologyapproach AT christianrvoolstra stingrayvenomproteinsmechanismsofactionrevealedusinganovelnetworkpharmacologyapproach AT stephankremb stingrayvenomproteinsmechanismsofactionrevealedusinganovelnetworkpharmacologyapproach AT thomaswilke stingrayvenomproteinsmechanismsofactionrevealedusinganovelnetworkpharmacologyapproach AT andreasvilcinskas stingrayvenomproteinsmechanismsofactionrevealedusinganovelnetworkpharmacologyapproach |