Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | https://repositorio.unifesp.br/handle/11600/56191 http://dx.doi.org/10.1016/j.ijpddr.2016.02.003 |
Resumo: | Parasitic diseases cause similar to 500,000 deaths annually and remain a major challenge for therapeutic development. Using a rational design based approach, we developed peptide inhibitors with anti-parasitic activity that were derived from the sequences of parasite scaffold proteins LACK (Leishmania's receptor for activated C-kinase) and TRACK (Trypanosoma receptor for activated C-kinase). We hypothesized that sequences in LACK and TRACK that are conserved in the parasites, but not in the mammalian ortholog, RACK (Receptor for activated C-kinase), may be interaction sites for signaling proteins that are critical for the parasites' viability. One of these peptides exhibited leishmanicidal and trypanocidal activity in culture. Moreover, in infected mice, this peptide was also effective in reducing parasitemia and increasing survival without toxic effects. The identified peptide is a promising new anti-parasitic drug lead, as its unique features may limit toxicity and drug-resistance, thus overcoming central limitations of most anti-parasitic drugs. (C) 2016 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology. |
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Qvit, NirSchechtman, DeborahPena, Darlene AparecidaBerti, Denise AparecidaSoares, Chrislaine OliveiraMiao, QianqianLiang, Liying (Annie)Baron, Lauren A.Teh-Poot, ChristianMartinez-Vega, PedroRamirez-Sierra, Maria JesusChurchill, EricCunningham, Anna D.Malkovskiy, Andrey V.Federspiel, Nancy A.Gozzo, Fabio CesarTorrecilhas, Ana Claudia [UNIFESP]Manso Alves, Maria JuliaJardim, ArmandoMomar, NdaoDumonteil, EricMochly-Rosen, Daria2020-07-22T13:23:21Z2020-07-22T13:23:21Z2016International Journal For Parasitology-Drugs And Drug Resistance. Oxford, v. 6, n. 1, p. 74-84, 2016.2211-3207https://repositorio.unifesp.br/handle/11600/56191http://dx.doi.org/10.1016/j.ijpddr.2016.02.003WOS000372717200008.pdf10.1016/j.ijpddr.2016.02.003WOS:000372717200008Parasitic diseases cause similar to 500,000 deaths annually and remain a major challenge for therapeutic development. Using a rational design based approach, we developed peptide inhibitors with anti-parasitic activity that were derived from the sequences of parasite scaffold proteins LACK (Leishmania's receptor for activated C-kinase) and TRACK (Trypanosoma receptor for activated C-kinase). We hypothesized that sequences in LACK and TRACK that are conserved in the parasites, but not in the mammalian ortholog, RACK (Receptor for activated C-kinase), may be interaction sites for signaling proteins that are critical for the parasites' viability. One of these peptides exhibited leishmanicidal and trypanocidal activity in culture. Moreover, in infected mice, this peptide was also effective in reducing parasitemia and increasing survival without toxic effects. The identified peptide is a promising new anti-parasitic drug lead, as its unique features may limit toxicity and drug-resistance, thus overcoming central limitations of most anti-parasitic drugs. (C) 2016 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology.National Institutes of HealthStanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 USAUniv Sao Paulo, Inst Quim, Dept Bioquim, BR-05508 Sao Paulo, SP, BrazilMcGill Univ, Res Inst, Natl Reference Ctr Parasitol, Montreal, PQ, CanadaUniv Autonoma Yucatan, Ctr Invest Reg Dr Hideyo Noguchi, Parasitol Lab, Merida, Yucatan, MexicoStanford Univ, Biomat & Adv Drug Delivery Lab, Stanford, CA 94305 USAUniv Estadual Campinas, Inst Chem, Campinas, SP, BrazilUniv Fed Sao Paulo, Dept Ciencias Biol, Campus Diadema, Sao Paulo, BrazilMcGill Univ, Inst Parasitol, Quebec City, PQ, CanadaMcGill Univ, Ctr Host Parasite Interact, Quebec City, PQ, CanadaUniv Fed Sao Paulo, Dept Ciencias Biol, Campus Diadema, Sao Paulo, BrazilNIH: TW008781-01C-IDEANIH: AI078505Web of Science74-84engElsevier Sci LtdInternational Journal For Parasitology-Drugs And Drug ResistanceChagas diseaseLeishmaniasisPeptideLACKTRACKScaffold proteinScaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitorsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleOxford61info:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESPORIGINALWOS000372717200008.pdfapplication/pdf1489408${dspace.ui.url}/bitstream/11600/56191/1/WOS000372717200008.pdf6df8eefb0b212698415e862d86ac1743MD51open accessTEXTWOS000372717200008.pdf.txtWOS000372717200008.pdf.txtExtracted texttext/plain68855${dspace.ui.url}/bitstream/11600/56191/8/WOS000372717200008.pdf.txt96b115713182424e0a1686eec6c5b2e7MD58open accessTHUMBNAILWOS000372717200008.pdf.jpgWOS000372717200008.pdf.jpgIM Thumbnailimage/jpeg7458${dspace.ui.url}/bitstream/11600/56191/10/WOS000372717200008.pdf.jpg46c4e17adb1415a45880ac23ccf18447MD510open access11600/561912023-06-05 19:26:49.091open accessoai:repositorio.unifesp.br:11600/56191Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652023-06-05T22:26:49Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors |
title |
Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors |
spellingShingle |
Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors Qvit, Nir Chagas disease Leishmaniasis Peptide LACK TRACK Scaffold protein |
title_short |
Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors |
title_full |
Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors |
title_fullStr |
Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors |
title_full_unstemmed |
Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors |
title_sort |
Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors |
author |
Qvit, Nir |
author_facet |
Qvit, Nir Schechtman, Deborah Pena, Darlene Aparecida Berti, Denise Aparecida Soares, Chrislaine Oliveira Miao, Qianqian Liang, Liying (Annie) Baron, Lauren A. Teh-Poot, Christian Martinez-Vega, Pedro Ramirez-Sierra, Maria Jesus Churchill, Eric Cunningham, Anna D. Malkovskiy, Andrey V. Federspiel, Nancy A. Gozzo, Fabio Cesar Torrecilhas, Ana Claudia [UNIFESP] Manso Alves, Maria Julia Jardim, Armando Momar, Ndao Dumonteil, Eric Mochly-Rosen, Daria |
author_role |
author |
author2 |
Schechtman, Deborah Pena, Darlene Aparecida Berti, Denise Aparecida Soares, Chrislaine Oliveira Miao, Qianqian Liang, Liying (Annie) Baron, Lauren A. Teh-Poot, Christian Martinez-Vega, Pedro Ramirez-Sierra, Maria Jesus Churchill, Eric Cunningham, Anna D. Malkovskiy, Andrey V. Federspiel, Nancy A. Gozzo, Fabio Cesar Torrecilhas, Ana Claudia [UNIFESP] Manso Alves, Maria Julia Jardim, Armando Momar, Ndao Dumonteil, Eric Mochly-Rosen, Daria |
author2_role |
author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Qvit, Nir Schechtman, Deborah Pena, Darlene Aparecida Berti, Denise Aparecida Soares, Chrislaine Oliveira Miao, Qianqian Liang, Liying (Annie) Baron, Lauren A. Teh-Poot, Christian Martinez-Vega, Pedro Ramirez-Sierra, Maria Jesus Churchill, Eric Cunningham, Anna D. Malkovskiy, Andrey V. Federspiel, Nancy A. Gozzo, Fabio Cesar Torrecilhas, Ana Claudia [UNIFESP] Manso Alves, Maria Julia Jardim, Armando Momar, Ndao Dumonteil, Eric Mochly-Rosen, Daria |
dc.subject.eng.fl_str_mv |
Chagas disease Leishmaniasis Peptide LACK TRACK Scaffold protein |
topic |
Chagas disease Leishmaniasis Peptide LACK TRACK Scaffold protein |
description |
Parasitic diseases cause similar to 500,000 deaths annually and remain a major challenge for therapeutic development. Using a rational design based approach, we developed peptide inhibitors with anti-parasitic activity that were derived from the sequences of parasite scaffold proteins LACK (Leishmania's receptor for activated C-kinase) and TRACK (Trypanosoma receptor for activated C-kinase). We hypothesized that sequences in LACK and TRACK that are conserved in the parasites, but not in the mammalian ortholog, RACK (Receptor for activated C-kinase), may be interaction sites for signaling proteins that are critical for the parasites' viability. One of these peptides exhibited leishmanicidal and trypanocidal activity in culture. Moreover, in infected mice, this peptide was also effective in reducing parasitemia and increasing survival without toxic effects. The identified peptide is a promising new anti-parasitic drug lead, as its unique features may limit toxicity and drug-resistance, thus overcoming central limitations of most anti-parasitic drugs. (C) 2016 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology. |
publishDate |
2016 |
dc.date.issued.fl_str_mv |
2016 |
dc.date.accessioned.fl_str_mv |
2020-07-22T13:23:21Z |
dc.date.available.fl_str_mv |
2020-07-22T13:23:21Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
International Journal For Parasitology-Drugs And Drug Resistance. Oxford, v. 6, n. 1, p. 74-84, 2016. |
dc.identifier.uri.fl_str_mv |
https://repositorio.unifesp.br/handle/11600/56191 http://dx.doi.org/10.1016/j.ijpddr.2016.02.003 |
dc.identifier.issn.none.fl_str_mv |
2211-3207 |
dc.identifier.file.none.fl_str_mv |
WOS000372717200008.pdf |
dc.identifier.doi.none.fl_str_mv |
10.1016/j.ijpddr.2016.02.003 |
dc.identifier.wos.none.fl_str_mv |
WOS:000372717200008 |
identifier_str_mv |
International Journal For Parasitology-Drugs And Drug Resistance. Oxford, v. 6, n. 1, p. 74-84, 2016. 2211-3207 WOS000372717200008.pdf 10.1016/j.ijpddr.2016.02.003 WOS:000372717200008 |
url |
https://repositorio.unifesp.br/handle/11600/56191 http://dx.doi.org/10.1016/j.ijpddr.2016.02.003 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartof.none.fl_str_mv |
International Journal For Parasitology-Drugs And Drug Resistance |
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info:eu-repo/semantics/openAccess |
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openAccess |
dc.format.none.fl_str_mv |
74-84 |
dc.coverage.none.fl_str_mv |
Oxford |
dc.publisher.none.fl_str_mv |
Elsevier Sci Ltd |
publisher.none.fl_str_mv |
Elsevier Sci Ltd |
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reponame:Repositório Institucional da UNIFESP instname:Universidade Federal de São Paulo (UNIFESP) instacron:UNIFESP |
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Universidade Federal de São Paulo (UNIFESP) |
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UNIFESP |
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UNIFESP |
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Repositório Institucional da UNIFESP |
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