Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum

Autores
Bertoldo, Jean Borges; Chiaradia Delatorre, Louise Domeneghini; Mascarello, Alessandra; Leal, Paulo César; Sechini Cordeiro, Marlon Norberto; Nunes, Ricardo José; Salas Sarduy, Emir; Rosenthal, Philip Jon; Terenzi, Hernán
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Falcipain-2 (FP-2) is a key cysteine protease from the malaria parasite Plasmodium falciparum. Many previous studies have identified FP-2 inhibitors; however, none has yet met the criteria for an antimalarial drug candidate. In this work, we assayed an in-house library of non-peptidic organic compounds, including (E)-chalcones, (E)-N'-benzylidene-benzohydrazides and alkyl-esters of gallic acid, and assessed the activity toward FP-2 and their mechanisms of inhibition. The (E)-chalcones 48, 54 and 66 showed the lowest IC50 values (8.5±0.8μM, 9.5±0.2μM and 4.9±1.3μM, respectively). The best inhibitor (compound 66) demonstrated non-competitive inhibition, and using mass spectrometry and fluorescence spectroscopy assays, we suggest a potential allosteric site for the interaction of this compound, located between the catalytic site and the hemoglobin binding arm in FP-2. We combined structural biology tools and mass spectrometry to characterize the inhibition mechanisms of novel compounds targeting FP-2.
Fil: Bertoldo, Jean Borges. Universidade Federal de Santa Catarina; Brasil
Fil: Chiaradia Delatorre, Louise Domeneghini. Universidade Federal de Santa Catarina; Brasil
Fil: Mascarello, Alessandra. Universidade Federal de Santa Catarina; Brasil
Fil: Leal, Paulo César. Universidade Federal de Santa Catarina; Brasil
Fil: Sechini Cordeiro, Marlon Norberto. Universidade Federal de Santa Catarina; Brasil
Fil: Nunes, Ricardo José. Universidade Federal de Santa Catarina; Brasil
Fil: Salas Sarduy, Emir. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de La Habana; Cuba
Fil: Rosenthal, Philip Jon. University of California; Estados Unidos
Fil: Terenzi, Hernán. Universidade Federal de Santa Catarina; Brasil
Materia
FALCIPAIN 2
PLASMODIUM
MALARIA
CHALCONES
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/95659
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/95659
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparumBertoldo, Jean BorgesChiaradia Delatorre, Louise DomeneghiniMascarello, AlessandraLeal, Paulo CésarSechini Cordeiro, Marlon NorbertoNunes, Ricardo JoséSalas Sarduy, EmirRosenthal, Philip JonTerenzi, HernánFALCIPAIN 2PLASMODIUMMALARIACHALCONEShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Falcipain-2 (FP-2) is a key cysteine protease from the malaria parasite Plasmodium falciparum. Many previous studies have identified FP-2 inhibitors; however, none has yet met the criteria for an antimalarial drug candidate. In this work, we assayed an in-house library of non-peptidic organic compounds, including (E)-chalcones, (E)-N'-benzylidene-benzohydrazides and alkyl-esters of gallic acid, and assessed the activity toward FP-2 and their mechanisms of inhibition. The (E)-chalcones 48, 54 and 66 showed the lowest IC50 values (8.5±0.8μM, 9.5±0.2μM and 4.9±1.3μM, respectively). The best inhibitor (compound 66) demonstrated non-competitive inhibition, and using mass spectrometry and fluorescence spectroscopy assays, we suggest a potential allosteric site for the interaction of this compound, located between the catalytic site and the hemoglobin binding arm in FP-2. We combined structural biology tools and mass spectrometry to characterize the inhibition mechanisms of novel compounds targeting FP-2.Fil: Bertoldo, Jean Borges. Universidade Federal de Santa Catarina; BrasilFil: Chiaradia Delatorre, Louise Domeneghini. Universidade Federal de Santa Catarina; BrasilFil: Mascarello, Alessandra. Universidade Federal de Santa Catarina; BrasilFil: Leal, Paulo César. Universidade Federal de Santa Catarina; BrasilFil: Sechini Cordeiro, Marlon Norberto. Universidade Federal de Santa Catarina; BrasilFil: Nunes, Ricardo José. Universidade Federal de Santa Catarina; BrasilFil: Salas Sarduy, Emir. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de La Habana; CubaFil: Rosenthal, Philip Jon. University of California; Estados UnidosFil: Terenzi, Hernán. Universidade Federal de Santa Catarina; BrasilTaylor & Francis Ltd2015-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/95659Bertoldo, Jean Borges; Chiaradia Delatorre, Louise Domeneghini; Mascarello, Alessandra; Leal, Paulo César; Sechini Cordeiro, Marlon Norberto; et al.; Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum; Taylor & Francis Ltd; Journal of Enzyme Inhibition and Medicinal Chemistry; 30; 2; 2-2015; 299-3071475-63661475-6374CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.tandfonline.com/doi/full/10.3109/14756366.2014.920839info:eu-repo/semantics/altIdentifier/doi/10.3109/14756366.2014.920839info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:04:41Zoai:ri.conicet.gov.ar:11336/95659instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:04:41.541CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum
title Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum
spellingShingle Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum
Bertoldo, Jean Borges
FALCIPAIN 2
PLASMODIUM
MALARIA
CHALCONES
title_short Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum
title_full Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum
title_fullStr Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum
title_full_unstemmed Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum
title_sort Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum
dc.creator.none.fl_str_mv Bertoldo, Jean Borges
Chiaradia Delatorre, Louise Domeneghini
Mascarello, Alessandra
Leal, Paulo César
Sechini Cordeiro, Marlon Norberto
Nunes, Ricardo José
Salas Sarduy, Emir
Rosenthal, Philip Jon
Terenzi, Hernán
author Bertoldo, Jean Borges
author_facet Bertoldo, Jean Borges
Chiaradia Delatorre, Louise Domeneghini
Mascarello, Alessandra
Leal, Paulo César
Sechini Cordeiro, Marlon Norberto
Nunes, Ricardo José
Salas Sarduy, Emir
Rosenthal, Philip Jon
Terenzi, Hernán
author_role author
author2 Chiaradia Delatorre, Louise Domeneghini
Mascarello, Alessandra
Leal, Paulo César
Sechini Cordeiro, Marlon Norberto
Nunes, Ricardo José
Salas Sarduy, Emir
Rosenthal, Philip Jon
Terenzi, Hernán
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv FALCIPAIN 2
PLASMODIUM
MALARIA
CHALCONES
topic FALCIPAIN 2
PLASMODIUM
MALARIA
CHALCONES
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Falcipain-2 (FP-2) is a key cysteine protease from the malaria parasite Plasmodium falciparum. Many previous studies have identified FP-2 inhibitors; however, none has yet met the criteria for an antimalarial drug candidate. In this work, we assayed an in-house library of non-peptidic organic compounds, including (E)-chalcones, (E)-N'-benzylidene-benzohydrazides and alkyl-esters of gallic acid, and assessed the activity toward FP-2 and their mechanisms of inhibition. The (E)-chalcones 48, 54 and 66 showed the lowest IC50 values (8.5±0.8μM, 9.5±0.2μM and 4.9±1.3μM, respectively). The best inhibitor (compound 66) demonstrated non-competitive inhibition, and using mass spectrometry and fluorescence spectroscopy assays, we suggest a potential allosteric site for the interaction of this compound, located between the catalytic site and the hemoglobin binding arm in FP-2. We combined structural biology tools and mass spectrometry to characterize the inhibition mechanisms of novel compounds targeting FP-2.
Fil: Bertoldo, Jean Borges. Universidade Federal de Santa Catarina; Brasil
Fil: Chiaradia Delatorre, Louise Domeneghini. Universidade Federal de Santa Catarina; Brasil
Fil: Mascarello, Alessandra. Universidade Federal de Santa Catarina; Brasil
Fil: Leal, Paulo César. Universidade Federal de Santa Catarina; Brasil
Fil: Sechini Cordeiro, Marlon Norberto. Universidade Federal de Santa Catarina; Brasil
Fil: Nunes, Ricardo José. Universidade Federal de Santa Catarina; Brasil
Fil: Salas Sarduy, Emir. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de La Habana; Cuba
Fil: Rosenthal, Philip Jon. University of California; Estados Unidos
Fil: Terenzi, Hernán. Universidade Federal de Santa Catarina; Brasil
description Falcipain-2 (FP-2) is a key cysteine protease from the malaria parasite Plasmodium falciparum. Many previous studies have identified FP-2 inhibitors; however, none has yet met the criteria for an antimalarial drug candidate. In this work, we assayed an in-house library of non-peptidic organic compounds, including (E)-chalcones, (E)-N'-benzylidene-benzohydrazides and alkyl-esters of gallic acid, and assessed the activity toward FP-2 and their mechanisms of inhibition. The (E)-chalcones 48, 54 and 66 showed the lowest IC50 values (8.5±0.8μM, 9.5±0.2μM and 4.9±1.3μM, respectively). The best inhibitor (compound 66) demonstrated non-competitive inhibition, and using mass spectrometry and fluorescence spectroscopy assays, we suggest a potential allosteric site for the interaction of this compound, located between the catalytic site and the hemoglobin binding arm in FP-2. We combined structural biology tools and mass spectrometry to characterize the inhibition mechanisms of novel compounds targeting FP-2.
publishDate 2015
dc.date.none.fl_str_mv 2015-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/95659
Bertoldo, Jean Borges; Chiaradia Delatorre, Louise Domeneghini; Mascarello, Alessandra; Leal, Paulo César; Sechini Cordeiro, Marlon Norberto; et al.; Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum; Taylor & Francis Ltd; Journal of Enzyme Inhibition and Medicinal Chemistry; 30; 2; 2-2015; 299-307
1475-6366
1475-6374
CONICET Digital
CONICET
url http://hdl.handle.net/11336/95659
identifier_str_mv Bertoldo, Jean Borges; Chiaradia Delatorre, Louise Domeneghini; Mascarello, Alessandra; Leal, Paulo César; Sechini Cordeiro, Marlon Norberto; et al.; Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum; Taylor & Francis Ltd; Journal of Enzyme Inhibition and Medicinal Chemistry; 30; 2; 2-2015; 299-307
1475-6366
1475-6374
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.tandfonline.com/doi/full/10.3109/14756366.2014.920839
info:eu-repo/semantics/altIdentifier/doi/10.3109/14756366.2014.920839
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Taylor & Francis Ltd
publisher.none.fl_str_mv Taylor & Francis Ltd
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1846781309514416128
score 12.982451

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