In silico-guided drug repurposing: identification of non-competitive inhibitors of Trypanosoma cruzi and Plasmodium falciparum cysteine proteases

Autores
Salas Sarduy, Emir; Alberca, Lucas Nicolás; Bellera, Carolina Leticia; Talevi, Alan
Año de publicación
2020
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Abstract/Resumen: Trypanosoma cruzi and Plasmodium falciparum are the etiologic agents of Chagas disease and Malaria, respectively. Cysteine proteases play key roles in the pathogenesis and survival of these parasites, such as cell/tissue penetration, hydrolysis of host or parasite proteins, autophagy, and evasion or modulation of the host immune response, being considered attractive chemotherapeutic targets. Cruzipain (Cz) and Falcipain-2 (FP-2) are two essential cysteine proteases of such organisms. Previously, we have found that methacycline (a member of tetracycline family) is a non-competitive inhibitor of FP-2 (Alberca et al. 2019). In this study our objective has been the characterization of six tetracycline analogues (tetracycline, minocycline, doxycycline, oxytetracycline, chlortetracycline and methacycline) as inhibitors of these cysteine proteases by in silico and in vitro determinations. First, we used bioinformatic tools to predict possible allosteric binding pockets; subsequently, we studied their possible interactions with these proteases by molecular docking simulations. The structures of the enzymes were obtained from the Protein data bank. Finally, we proceed to inhibition studies on the purified enzymes, which confirmed that these family of antibiotics inhibit cysteine proteases in a reversible, non-competitive manner, with Ki values in the mid-micromolar order. Our results provide further evidence on the utility of computational tools as a rational basis for systematic drug repurposing.
Fil: Salas Sarduy, Emir. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Alberca, Lucas Nicolás. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Bellera, Carolina Leticia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina
Fil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Reunión anual de Sociedades Biociencia
Mar del Plata
Argentina
Sociedad Argentina de Investigación Clínica
Asociación Argentina de Farmacología Experimental
Sociedad Argentina de Biología
Sociedad Argentina de Protozoología
Asociación Argentina de Nanomedicinas
Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
Materia
CYSTEIN PROTEASES
MALARIA
DRUG REPOSITIONING
CHAGAS
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:11336/154105
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/154105
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling In silico-guided drug repurposing: identification of non-competitive inhibitors of Trypanosoma cruzi and Plasmodium falciparum cysteine proteasesSalas Sarduy, EmirAlberca, Lucas NicolásBellera, Carolina LeticiaTalevi, AlanCYSTEIN PROTEASESMALARIADRUG REPOSITIONINGCHAGAShttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Abstract/Resumen: Trypanosoma cruzi and Plasmodium falciparum are the etiologic agents of Chagas disease and Malaria, respectively. Cysteine proteases play key roles in the pathogenesis and survival of these parasites, such as cell/tissue penetration, hydrolysis of host or parasite proteins, autophagy, and evasion or modulation of the host immune response, being considered attractive chemotherapeutic targets. Cruzipain (Cz) and Falcipain-2 (FP-2) are two essential cysteine proteases of such organisms. Previously, we have found that methacycline (a member of tetracycline family) is a non-competitive inhibitor of FP-2 (Alberca et al. 2019). In this study our objective has been the characterization of six tetracycline analogues (tetracycline, minocycline, doxycycline, oxytetracycline, chlortetracycline and methacycline) as inhibitors of these cysteine proteases by in silico and in vitro determinations. First, we used bioinformatic tools to predict possible allosteric binding pockets; subsequently, we studied their possible interactions with these proteases by molecular docking simulations. The structures of the enzymes were obtained from the Protein data bank. Finally, we proceed to inhibition studies on the purified enzymes, which confirmed that these family of antibiotics inhibit cysteine proteases in a reversible, non-competitive manner, with Ki values in the mid-micromolar order. Our results provide further evidence on the utility of computational tools as a rational basis for systematic drug repurposing.Fil: Salas Sarduy, Emir. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Alberca, Lucas Nicolás. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Bellera, Carolina Leticia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; ArgentinaFil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaReunión anual de Sociedades BiocienciaMar del PlataArgentinaSociedad Argentina de Investigación ClínicaAsociación Argentina de Farmacología ExperimentalSociedad Argentina de BiologíaSociedad Argentina de ProtozoologíaAsociación Argentina de NanomedicinasAsociación Argentina de Ciencia y Tecnología de Animales de LaboratorioFundación Revista Medicina2020info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/154105In silico-guided drug repurposing: identification of non-competitive inhibitors of Trypanosoma cruzi and Plasmodium falciparum cysteine proteases; Reunión anual de Sociedades Biociencia; Mar del Plata; Argentina; 2019; 1-60025-76801669-9106CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://medicinabuenosaires.com/revistas/vol79-19/s4/vol79_s4.pdfNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:43:47Zoai:ri.conicet.gov.ar:11336/154105instacron: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:34982025-09-03 09:43:48.174CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv In silico-guided drug repurposing: identification of non-competitive inhibitors of Trypanosoma cruzi and Plasmodium falciparum cysteine proteases
title In silico-guided drug repurposing: identification of non-competitive inhibitors of Trypanosoma cruzi and Plasmodium falciparum cysteine proteases
spellingShingle In silico-guided drug repurposing: identification of non-competitive inhibitors of Trypanosoma cruzi and Plasmodium falciparum cysteine proteases
Salas Sarduy, Emir
CYSTEIN PROTEASES
MALARIA
DRUG REPOSITIONING
CHAGAS
title_short In silico-guided drug repurposing: identification of non-competitive inhibitors of Trypanosoma cruzi and Plasmodium falciparum cysteine proteases
title_full In silico-guided drug repurposing: identification of non-competitive inhibitors of Trypanosoma cruzi and Plasmodium falciparum cysteine proteases
title_fullStr In silico-guided drug repurposing: identification of non-competitive inhibitors of Trypanosoma cruzi and Plasmodium falciparum cysteine proteases
title_full_unstemmed In silico-guided drug repurposing: identification of non-competitive inhibitors of Trypanosoma cruzi and Plasmodium falciparum cysteine proteases
title_sort In silico-guided drug repurposing: identification of non-competitive inhibitors of Trypanosoma cruzi and Plasmodium falciparum cysteine proteases
dc.creator.none.fl_str_mv Salas Sarduy, Emir
Alberca, Lucas Nicolás
Bellera, Carolina Leticia
Talevi, Alan
author Salas Sarduy, Emir
author_facet Salas Sarduy, Emir
Alberca, Lucas Nicolás
Bellera, Carolina Leticia
Talevi, Alan
author_role author
author2 Alberca, Lucas Nicolás
Bellera, Carolina Leticia
Talevi, Alan
author2_role author
author
author
dc.subject.none.fl_str_mv CYSTEIN PROTEASES
MALARIA
DRUG REPOSITIONING
CHAGAS
topic CYSTEIN PROTEASES
MALARIA
DRUG REPOSITIONING
CHAGAS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Abstract/Resumen: Trypanosoma cruzi and Plasmodium falciparum are the etiologic agents of Chagas disease and Malaria, respectively. Cysteine proteases play key roles in the pathogenesis and survival of these parasites, such as cell/tissue penetration, hydrolysis of host or parasite proteins, autophagy, and evasion or modulation of the host immune response, being considered attractive chemotherapeutic targets. Cruzipain (Cz) and Falcipain-2 (FP-2) are two essential cysteine proteases of such organisms. Previously, we have found that methacycline (a member of tetracycline family) is a non-competitive inhibitor of FP-2 (Alberca et al. 2019). In this study our objective has been the characterization of six tetracycline analogues (tetracycline, minocycline, doxycycline, oxytetracycline, chlortetracycline and methacycline) as inhibitors of these cysteine proteases by in silico and in vitro determinations. First, we used bioinformatic tools to predict possible allosteric binding pockets; subsequently, we studied their possible interactions with these proteases by molecular docking simulations. The structures of the enzymes were obtained from the Protein data bank. Finally, we proceed to inhibition studies on the purified enzymes, which confirmed that these family of antibiotics inhibit cysteine proteases in a reversible, non-competitive manner, with Ki values in the mid-micromolar order. Our results provide further evidence on the utility of computational tools as a rational basis for systematic drug repurposing.
Fil: Salas Sarduy, Emir. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Alberca, Lucas Nicolás. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Bellera, Carolina Leticia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina
Fil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Reunión anual de Sociedades Biociencia
Mar del Plata
Argentina
Sociedad Argentina de Investigación Clínica
Asociación Argentina de Farmacología Experimental
Sociedad Argentina de Biología
Sociedad Argentina de Protozoología
Asociación Argentina de Nanomedicinas
Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
description Abstract/Resumen: Trypanosoma cruzi and Plasmodium falciparum are the etiologic agents of Chagas disease and Malaria, respectively. Cysteine proteases play key roles in the pathogenesis and survival of these parasites, such as cell/tissue penetration, hydrolysis of host or parasite proteins, autophagy, and evasion or modulation of the host immune response, being considered attractive chemotherapeutic targets. Cruzipain (Cz) and Falcipain-2 (FP-2) are two essential cysteine proteases of such organisms. Previously, we have found that methacycline (a member of tetracycline family) is a non-competitive inhibitor of FP-2 (Alberca et al. 2019). In this study our objective has been the characterization of six tetracycline analogues (tetracycline, minocycline, doxycycline, oxytetracycline, chlortetracycline and methacycline) as inhibitors of these cysteine proteases by in silico and in vitro determinations. First, we used bioinformatic tools to predict possible allosteric binding pockets; subsequently, we studied their possible interactions with these proteases by molecular docking simulations. The structures of the enzymes were obtained from the Protein data bank. Finally, we proceed to inhibition studies on the purified enzymes, which confirmed that these family of antibiotics inhibit cysteine proteases in a reversible, non-competitive manner, with Ki values in the mid-micromolar order. Our results provide further evidence on the utility of computational tools as a rational basis for systematic drug repurposing.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Reunión
Journal
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/154105
In silico-guided drug repurposing: identification of non-competitive inhibitors of Trypanosoma cruzi and Plasmodium falciparum cysteine proteases; Reunión anual de Sociedades Biociencia; Mar del Plata; Argentina; 2019; 1-6
0025-7680
1669-9106
CONICET Digital
CONICET
url http://hdl.handle.net/11336/154105
identifier_str_mv In silico-guided drug repurposing: identification of non-competitive inhibitors of Trypanosoma cruzi and Plasmodium falciparum cysteine proteases; Reunión anual de Sociedades Biociencia; Mar del Plata; Argentina; 2019; 1-6
0025-7680
1669-9106
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://medicinabuenosaires.com/revistas/vol79-19/s4/vol79_s4.pdf
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
application/pdf
dc.coverage.none.fl_str_mv Nacional
dc.publisher.none.fl_str_mv Fundación Revista Medicina
publisher.none.fl_str_mv Fundación Revista Medicina
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
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