Targeting Loxosceles spider Sphingomyelinase D with small-molecule inhibitors as a potential therapeutic approach for loxoscelism
Loxosceles spiders’ venoms consist of a mixture of proteins, including the sphingomyelinases D (SMases D), which are the main toxic components responsible for local and systemic effects in human envenomation. Herein, based on the structural information of SMase D from Loxosceles laeta spider venom a...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | http://dx.doi.org/10.1080/14756366.2018.1546698 |
| _version_ | 1818032162834743296 |
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| author | Priscila Hess Lopes Mário T. Murakami Fernanda C. V. Portaro Kerly Fernanda Mesquita Pasqualoto Carmen van den Berg Denise V. Tambourgi |
| author_facet | Priscila Hess Lopes Mário T. Murakami Fernanda C. V. Portaro Kerly Fernanda Mesquita Pasqualoto Carmen van den Berg Denise V. Tambourgi |
| author_sort | Priscila Hess Lopes |
| collection | DOAJ |
| description | Loxosceles spiders’ venoms consist of a mixture of proteins, including the sphingomyelinases D (SMases D), which are the main toxic components responsible for local and systemic effects in human envenomation. Herein, based on the structural information of SMase D from Loxosceles laeta spider venom and virtual docking-based screening approach, three benzene sulphonate compounds (named 1, 5 and 6) were identified as potential Loxosceles SMase D inhibitors. All compounds inhibited the hydrolysis of the sphingomyelin substrate by both recombinant and native SMases D. Compounds 5 and 6 acted as SMases D uncompetitive inhibitors with Ki values of 0.49 µM and 0.59 µM, respectively. Compound 1 is a mixed type inhibitor, and presented a Ki value of 0.54 µM. In addition, the three compounds inhibited the binding of SMases D to human erythrocytes and the removal of glycophorin C from the cell surface, which are important events in the complement-dependent haemolysis induced by Loxosceles venom. Moreover, compounds 5 and 6 reduced the binding of SMases to human keratinocytes membrane and the venom induced cell death. Importantly, compounds 5 and 6 also controlled the development of the necrotic lesion in an in vivo model of loxoscelism. Together, our findings indicate that the novel SMase D inhibitors presented here are able to suppress both local and systemic reactions induced by Loxosceles venoms. Since the number of Loxosceles envenomation accidents is currently growing worldwide, our results indicate that both inhibitors are promising scaffolds for the rational design of new drugs targeting SMases D from these spiders. |
| first_indexed | 2024-12-10T06:03:00Z |
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| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-10T06:03:00Z |
| publishDate | 2019-01-01 |
| publisher | Taylor & Francis Group |
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| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-71a641201d154ec4a2292fbac0c96f282022-12-22T01:59:46ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742019-01-0134131032110.1080/14756366.2018.15466981546698Targeting Loxosceles spider Sphingomyelinase D with small-molecule inhibitors as a potential therapeutic approach for loxoscelismPriscila Hess Lopes0Mário T. Murakami1Fernanda C. V. Portaro2Kerly Fernanda Mesquita Pasqualoto3Carmen van den Berg4Denise V. Tambourgi5Butantan InstituteNational Centre for Research in Energy and MaterialsButantan InstituteUniversity of São PauloCardiff University, School of MedicineButantan InstituteLoxosceles spiders’ venoms consist of a mixture of proteins, including the sphingomyelinases D (SMases D), which are the main toxic components responsible for local and systemic effects in human envenomation. Herein, based on the structural information of SMase D from Loxosceles laeta spider venom and virtual docking-based screening approach, three benzene sulphonate compounds (named 1, 5 and 6) were identified as potential Loxosceles SMase D inhibitors. All compounds inhibited the hydrolysis of the sphingomyelin substrate by both recombinant and native SMases D. Compounds 5 and 6 acted as SMases D uncompetitive inhibitors with Ki values of 0.49 µM and 0.59 µM, respectively. Compound 1 is a mixed type inhibitor, and presented a Ki value of 0.54 µM. In addition, the three compounds inhibited the binding of SMases D to human erythrocytes and the removal of glycophorin C from the cell surface, which are important events in the complement-dependent haemolysis induced by Loxosceles venom. Moreover, compounds 5 and 6 reduced the binding of SMases to human keratinocytes membrane and the venom induced cell death. Importantly, compounds 5 and 6 also controlled the development of the necrotic lesion in an in vivo model of loxoscelism. Together, our findings indicate that the novel SMase D inhibitors presented here are able to suppress both local and systemic reactions induced by Loxosceles venoms. Since the number of Loxosceles envenomation accidents is currently growing worldwide, our results indicate that both inhibitors are promising scaffolds for the rational design of new drugs targeting SMases D from these spiders.http://dx.doi.org/10.1080/14756366.2018.1546698novel sphingomyelinase d inhibitorsloxosceles venomsmolecular docking simulationsprotein-ligand binding affinityloxoscelism |
| spellingShingle | Priscila Hess Lopes Mário T. Murakami Fernanda C. V. Portaro Kerly Fernanda Mesquita Pasqualoto Carmen van den Berg Denise V. Tambourgi Targeting Loxosceles spider Sphingomyelinase D with small-molecule inhibitors as a potential therapeutic approach for loxoscelism Journal of Enzyme Inhibition and Medicinal Chemistry novel sphingomyelinase d inhibitors loxosceles venoms molecular docking simulations protein-ligand binding affinity loxoscelism |
| title | Targeting Loxosceles spider Sphingomyelinase D with small-molecule inhibitors as a potential therapeutic approach for loxoscelism |
| title_full | Targeting Loxosceles spider Sphingomyelinase D with small-molecule inhibitors as a potential therapeutic approach for loxoscelism |
| title_fullStr | Targeting Loxosceles spider Sphingomyelinase D with small-molecule inhibitors as a potential therapeutic approach for loxoscelism |
| title_full_unstemmed | Targeting Loxosceles spider Sphingomyelinase D with small-molecule inhibitors as a potential therapeutic approach for loxoscelism |
| title_short | Targeting Loxosceles spider Sphingomyelinase D with small-molecule inhibitors as a potential therapeutic approach for loxoscelism |
| title_sort | targeting loxosceles spider sphingomyelinase d with small molecule inhibitors as a potential therapeutic approach for loxoscelism |
| topic | novel sphingomyelinase d inhibitors loxosceles venoms molecular docking simulations protein-ligand binding affinity loxoscelism |
| url | http://dx.doi.org/10.1080/14756366.2018.1546698 |
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