Inhibition of a Snake Venom Metalloproteinase by the Flavonoid Myricetin

ABSTRACT: Most of the snakebite envenomations in Central and South America are caused by species belonging to Bothrops genus. Their venom is composed mainly by zinc-dependent metalloproteinases, responsible of the hemorrhage characteristic of these envenomations. The aim of this study was to determi...

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Autores:
Pereañez Jiménez, Jaime Andrés
Preciado Rojo, Lina María
Rey Suárez, Paola
Núñez Rangel, Vitelbina
Comer, Jeffrey
Tipo de recurso:
Article of investigation
Fecha de publicación:
2018
Institución:
Universidad de Antioquia
Repositorio:
Repositorio UdeA
Idioma:
eng
OAI Identifier:
oai:bibliotecadigital.udea.edu.co:10495/20585
Acceso en línea:
http://hdl.handle.net/10495/20585
Palabra clave:
Flavonoides
Flavonoids
Venenos de Serpiente
Snake Venoms
Simulación de Dinámica Molecular
Molecular Dynamics Simulation
Inhibidores de la Metaloproteinasa de la Matriz
Matrix Metalloproteinase Inhibitors
Rights
openAccess
License
http://creativecommons.org/licenses/by/2.5/co/
id UDEA2_a8b4d37fd925e6ece0aac73610bf5971
oai_identifier_str oai:bibliotecadigital.udea.edu.co:10495/20585
network_acronym_str UDEA2
network_name_str Repositorio UdeA
repository_id_str
dc.title.spa.fl_str_mv Inhibition of a Snake Venom Metalloproteinase by the Flavonoid Myricetin
title Inhibition of a Snake Venom Metalloproteinase by the Flavonoid Myricetin
spellingShingle Inhibition of a Snake Venom Metalloproteinase by the Flavonoid Myricetin
Flavonoides
Flavonoids
Venenos de Serpiente
Snake Venoms
Simulación de Dinámica Molecular
Molecular Dynamics Simulation
Inhibidores de la Metaloproteinasa de la Matriz
Matrix Metalloproteinase Inhibitors
title_short Inhibition of a Snake Venom Metalloproteinase by the Flavonoid Myricetin
title_full Inhibition of a Snake Venom Metalloproteinase by the Flavonoid Myricetin
title_fullStr Inhibition of a Snake Venom Metalloproteinase by the Flavonoid Myricetin
title_full_unstemmed Inhibition of a Snake Venom Metalloproteinase by the Flavonoid Myricetin
title_sort Inhibition of a Snake Venom Metalloproteinase by the Flavonoid Myricetin
dc.creator.fl_str_mv Pereañez Jiménez, Jaime Andrés
Preciado Rojo, Lina María
Rey Suárez, Paola
Núñez Rangel, Vitelbina
Comer, Jeffrey
dc.contributor.author.none.fl_str_mv Pereañez Jiménez, Jaime Andrés
Preciado Rojo, Lina María
Rey Suárez, Paola
Núñez Rangel, Vitelbina
Comer, Jeffrey
dc.subject.decs.none.fl_str_mv Flavonoides
Flavonoids
Venenos de Serpiente
Snake Venoms
Simulación de Dinámica Molecular
Molecular Dynamics Simulation
Inhibidores de la Metaloproteinasa de la Matriz
Matrix Metalloproteinase Inhibitors
topic Flavonoides
Flavonoids
Venenos de Serpiente
Snake Venoms
Simulación de Dinámica Molecular
Molecular Dynamics Simulation
Inhibidores de la Metaloproteinasa de la Matriz
Matrix Metalloproteinase Inhibitors
description ABSTRACT: Most of the snakebite envenomations in Central and South America are caused by species belonging to Bothrops genus. Their venom is composed mainly by zinc-dependent metalloproteinases, responsible of the hemorrhage characteristic of these envenomations. The aim of this study was to determine the inhibitory ability of ten flavonoids on the in-vitro proteolytic activity of Bothrops atrox venom and on the hemorrhagic, edema-forming and myonecrotic activities of Batx-I, the most abundant metalloproteinase isolated from this venom. Myricetin was the most active compound, exhibiting an IC50 value of 150 µM and 1021 µM for the inhibition of proteolytic and hemorrhagic activity, respectively. Independent injection experiments, with a concentration of 1600 µM of myricetin administered locally, immediately after toxin injection, demonstrated a reduction of 28 ± 6% in the hemorrhagic lesion. Additionally, myricetin at concentrations 800, 1200 and 1600 µM promoted a reduction in plasma creatine kinase activity induced by Batx-I of 21 ± 2%, 60 ± 5% and 63 ± 2%, respectively. Molecular dynamics simulations coupled with the adaptive biasing method suggest that myricetin can bind to the metalloproteinase active site via formation of hydrogen bonds between the hydroxyl groups 3’, 4’ and 5’ of the benzyl moiety and amino acid Glu143 of the metalloproteinase. The hydroxyl substitution pattern of myricetin appears to be essential for its inhibitory activity. Based on this evidence, myricetin constitutes a candidate for the development of inhibitors to reduce local tissue damage in snakebite envenomation.
publishDate 2018
dc.date.issued.none.fl_str_mv 2018
dc.date.accessioned.none.fl_str_mv 2021-07-02T13:12:39Z
dc.date.available.none.fl_str_mv 2021-07-02T13:12:39Z
dc.type.spa.fl_str_mv info:eu-repo/semantics/article
dc.type.coarversion.fl_str_mv http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.hasversion.spa.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.coar.spa.fl_str_mv http://purl.org/coar/resource_type/c_2df8fbb1
dc.type.redcol.spa.fl_str_mv https://purl.org/redcol/resource_type/ART
dc.type.local.spa.fl_str_mv Artículo de investigación
format http://purl.org/coar/resource_type/c_2df8fbb1
status_str publishedVersion
dc.identifier.citation.spa.fl_str_mv Preciado, L., Comer, J., Núñez, V., Rey-Súarez, P., & Pereañez, J. (2018). Inhibition of a Snake Venom Metalloproteinase by the Flavonoid Myricetin. Molecules, 23(10), 2662. MDPI AG. Retrieved from http://dx.doi.org/10.3390/molecules23102662
dc.identifier.issn.none.fl_str_mv 1420-3049
dc.identifier.uri.none.fl_str_mv http://hdl.handle.net/10495/20585
dc.identifier.doi.none.fl_str_mv 10.3390/molecules23102662
identifier_str_mv Preciado, L., Comer, J., Núñez, V., Rey-Súarez, P., & Pereañez, J. (2018). Inhibition of a Snake Venom Metalloproteinase by the Flavonoid Myricetin. Molecules, 23(10), 2662. MDPI AG. Retrieved from http://dx.doi.org/10.3390/molecules23102662
1420-3049
10.3390/molecules23102662
url http://hdl.handle.net/10495/20585
dc.language.iso.spa.fl_str_mv eng
language eng
dc.relation.ispartofjournalabbrev.spa.fl_str_mv Molecules
dc.rights.spa.fl_str_mv info:eu-repo/semantics/openAccess
dc.rights.uri.*.fl_str_mv http://creativecommons.org/licenses/by/2.5/co/
dc.rights.accessrights.spa.fl_str_mv http://purl.org/coar/access_right/c_abf2
dc.rights.creativecommons.spa.fl_str_mv https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/2.5/co/
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.format.extent.spa.fl_str_mv 15
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv MDPI
dc.publisher.group.spa.fl_str_mv Toxinología Alternativas Terapéuticas y Alimentarias
dc.publisher.place.spa.fl_str_mv Basilea, Suiza
institution Universidad de Antioquia
bitstream.url.fl_str_mv http://bibliotecadigital.udea.edu.co/bitstream/10495/20585/1/Perea%c3%b1ezJaime_2018_SnakeVenomMetalloproteinase.pdf
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repository.name.fl_str_mv Repositorio Institucional Universidad de Antioquia
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spelling Pereañez Jiménez, Jaime AndrésPreciado Rojo, Lina MaríaRey Suárez, PaolaNúñez Rangel, VitelbinaComer, Jeffrey2021-07-02T13:12:39Z2021-07-02T13:12:39Z2018Preciado, L., Comer, J., Núñez, V., Rey-Súarez, P., & Pereañez, J. (2018). Inhibition of a Snake Venom Metalloproteinase by the Flavonoid Myricetin. Molecules, 23(10), 2662. MDPI AG. Retrieved from http://dx.doi.org/10.3390/molecules231026621420-3049http://hdl.handle.net/10495/2058510.3390/molecules23102662ABSTRACT: Most of the snakebite envenomations in Central and South America are caused by species belonging to Bothrops genus. Their venom is composed mainly by zinc-dependent metalloproteinases, responsible of the hemorrhage characteristic of these envenomations. The aim of this study was to determine the inhibitory ability of ten flavonoids on the in-vitro proteolytic activity of Bothrops atrox venom and on the hemorrhagic, edema-forming and myonecrotic activities of Batx-I, the most abundant metalloproteinase isolated from this venom. Myricetin was the most active compound, exhibiting an IC50 value of 150 µM and 1021 µM for the inhibition of proteolytic and hemorrhagic activity, respectively. Independent injection experiments, with a concentration of 1600 µM of myricetin administered locally, immediately after toxin injection, demonstrated a reduction of 28 ± 6% in the hemorrhagic lesion. Additionally, myricetin at concentrations 800, 1200 and 1600 µM promoted a reduction in plasma creatine kinase activity induced by Batx-I of 21 ± 2%, 60 ± 5% and 63 ± 2%, respectively. Molecular dynamics simulations coupled with the adaptive biasing method suggest that myricetin can bind to the metalloproteinase active site via formation of hydrogen bonds between the hydroxyl groups 3’, 4’ and 5’ of the benzyl moiety and amino acid Glu143 of the metalloproteinase. The hydroxyl substitution pattern of myricetin appears to be essential for its inhibitory activity. Based on this evidence, myricetin constitutes a candidate for the development of inhibitors to reduce local tissue damage in snakebite envenomation.COL001447615application/pdfengMDPIToxinología Alternativas Terapéuticas y AlimentariasBasilea, Suizainfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_2df8fbb1https://purl.org/redcol/resource_type/ARTArtículo de investigaciónhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/2.5/co/http://purl.org/coar/access_right/c_abf2https://creativecommons.org/licenses/by/4.0/Inhibition of a Snake Venom Metalloproteinase by the Flavonoid MyricetinFlavonoidesFlavonoidsVenenos de SerpienteSnake VenomsSimulación de Dinámica MolecularMolecular Dynamics SimulationInhibidores de la Metaloproteinasa de la MatrizMatrix Metalloproteinase InhibitorsMoleculesMolecules1152310ORIGINALPereañezJaime_2018_SnakeVenomMetalloproteinase.pdfPereañezJaime_2018_SnakeVenomMetalloproteinase.pdfArtículo de investigaciónapplication/pdf837907http://bibliotecadigital.udea.edu.co/bitstream/10495/20585/1/Perea%c3%b1ezJaime_2018_SnakeVenomMetalloproteinase.pdf68aad2c0684b93f0cf71235f82bdc68cMD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8927http://bibliotecadigital.udea.edu.co/bitstream/10495/20585/2/license_rdf1646d1f6b96dbbbc38035efc9239ac9cMD52LICENSElicense.txtlicense.txttext/plain; charset=utf-81748http://bibliotecadigital.udea.edu.co/bitstream/10495/20585/3/license.txt8a4605be74aa9ea9d79846c1fba20a33MD5310495/20585oai:bibliotecadigital.udea.edu.co:10495/205852021-07-02 08:19:17.973Repositorio Institucional Universidad de Antioquiaandres.perez@udea.edu.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