Triacontyl p-coumarate: An inhibitor of snake venom metalloproteinases |
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| Institution: | 1. Instituto de Genética e Bioquímica, Universidade Federal de Uberlândia, UFU, Uberlândia, MG, Brazil;2. Faculdade de Ciências Biológicas, Universidade Federal de Goiás, UFG, Jataí, GO, Brazil;3. Departamento de Química, Universidade Estadual do Sudoeste da Bahia, UESB, Jequié, BA, Brazil;4. Departamento de Física e Biofísica, Instituto de Biociências, Universidade Estadual Paulista, UNESP, Botucatu, SP, Brazil;5. Instituto Nacional de Ciências e Tecnologia, Nanobiofarmacêutica, Brazil;1. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, FCFRP-USP, Ribeirão Preto, SP, Brazil;2. Departamento de Genética e Evolução, Universidade Federal de São Carlos, UFSCAR, São Carlos, SP, Brazil;3. Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil;4. Instituto de Química, Universidade Estadual Paulista, UNESP, Araraquara, SP, Brazil;1. Post-Graduate Program in Pharmaceutical Sciences, University of Sorocaba (UNISO), Rodovia Raposo Tavares km 92.5, 18023-000, Sorocaba, SP, Brazil;2. Bioengineering Program, Technological and Scientific Institute, Brazil University, Rua Carolina Fonseca, 584/235, 08230-030, São Paulo, SP, Brazil;3. Department of Translational Medicine (Section of Pharmacology), Faculty of Medical Sciences, State University of Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, 13083-970, Campinas, SP, Brazil;4. Graduate Program in Environmental Sciences and Health, School of Medical, Pharmaceutical and Biomedical Sciences, Pontifical Catholic University of Goiás, Brazil;5. Laboratory of Toxinology and Cardiovascular Research, Graduate Program in Health Sciences, University of Western São Paulo, Brazil;6. Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica;1. Departamento de Farmacia, Facultad de Química, Mexico City 04510, Mexico;2. Departamento de Ecología y Recursos Naturales, Facultad de Ciencias, Mexico City 04510, Mexico;3. Instituto de Biología, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;1. Departmento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Autonoma de Mexico, Avenida Universidad, 2001, Colonia Chamilpa, Cuernavaca, Morelos, 62210, Mexico;2. Laboratorio Universitario de Proteómica, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Avenida Universidad, 2001, Apartado Postal 510-3, Cuernavaca, Morelos, 62210, Mexico;1. Departamento de Química, Universidade Federal de São Carlos (UFSCar), São Carlos, SP, Brazil;2. Departamento de Bioprocessos e Biotecnologia, Faculdade de Ciências Agrárias, Universidade Estadual Paulista (UNESP), Botucatu, SP, Brazil;3. Instituto de Biotecnologia, Universidade Estadual Paulista (UNESP), Botucatu, SP, Brazil;4. Departamento de Física e Biofísica, Instituto de Biociências, Universidade Estadual Paulista (UNESP), Botucatu, SP, Brazil;5. Departamento de Química, Universidade Federal de Lavras (UFLA), Lavras, MG, Brazil;6. Centro de Estudos de Biomoléculas Aplicadas à Saúde (CEBio), Fundação Oswaldo Cruz (FIOCRUZ), unidade Fiocruz Rondônia, Porto Velho, RO, Brazil;7. Departamento de Medicina, Universidade Federal de Rondônia (UNIR), Porto Velho, RO, Brazil |
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| Abstract: | Snake venom metalloproteinases (SVMPs) participate in a number of important biological, physiological and pathophysiological processes and are primarily responsible for the local tissue damage characteristic of viperid snake envenomations. The use of medicinal plant extracts as antidotes against animal venoms is an old practice, especially against snake envenomations. Such plants are sources of many pharmacologically active compounds and have been shown to antagonize the effects of some venoms and toxins. The present study explores the activity of triacontyl p-coumarate (PCT), an active compound isolated from root bark of Bombacopsis glabra vegetal extract (Bg), against harmful effects of Bothropoides pauloensis snake venom and isolated toxins (SVMPs or phospholipase A2). Before inhibition assays, Bg or PCT was incubated with venom or toxins at ratios of 1:1 and 1:5 (w/w; venom or isolated toxins/PCT) for 30 min at 37 °C. Treatment conditions were also assayed to simulate snakebite with PCT inoculated at either the same venom or toxin site. PCT neutralized fibrinogenolytic activity and plasmatic fibrinogen depletion induced by B. pauloensis venom or isolated toxin. PCT also efficiently inhibited the hemorrhagic (3MDH – minimum hemorrhagic dose injected i.d into mice) and myotoxic activities induced by Jararhagin, a metalloproteinase from B. jararaca at 1:5 ratio (toxin: inhibitor, w/w) when it was previously incubated with PCT and injected into mice or when PCT was administered after toxin injection. Docking simulations using data on a metalloproteinase (Neuwiedase) structure suggest that the binding between the protein and the inhibitor occurs mainly in the active site region causing blockade of the enzymatic reaction by displacement of catalytic water. Steric hindrance may also play a role in the mechanism since the PCT hydrophobic tail was found to interact with the loop associated with substrate anchorage. Thus, PCT may provide a alternative to complement ophidian envenomation treatments. |
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