Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors
Parasitic diseases cause ∼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...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-04-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320716300100 |
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DOAJ |
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English |
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Article |
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DOAJ |
| author |
Nir Qvit Deborah Schechtman Darlene Aparecida Pena Denise Aparecida Berti Chrislaine Oliveira Soares Qianqian Miao Liying (Annie) Liang Lauren A. Baron Christian Teh-Poot Pedro Martínez-Vega Maria Jesus Ramirez-Sierra Eric Churchill Anna D. Cunningham Andrey V. Malkovskiy Nancy A. Federspiel Fabio Cesar Gozzo Ana Claudia Torrecilhas Maria Julia Manso Alves Armando Jardim Ndao Momar Eric Dumonteil Daria Mochly-Rosen |
| spellingShingle |
Nir Qvit Deborah Schechtman Darlene Aparecida Pena Denise Aparecida Berti Chrislaine Oliveira Soares Qianqian Miao Liying (Annie) Liang Lauren A. Baron Christian Teh-Poot Pedro Martínez-Vega Maria Jesus Ramirez-Sierra Eric Churchill Anna D. Cunningham Andrey V. Malkovskiy Nancy A. Federspiel Fabio Cesar Gozzo Ana Claudia Torrecilhas Maria Julia Manso Alves Armando Jardim Ndao Momar Eric Dumonteil Daria Mochly-Rosen Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors International Journal for Parasitology: Drugs and Drug Resistance |
| author_facet |
Nir Qvit Deborah Schechtman Darlene Aparecida Pena Denise Aparecida Berti Chrislaine Oliveira Soares Qianqian Miao Liying (Annie) Liang Lauren A. Baron Christian Teh-Poot Pedro Martínez-Vega Maria Jesus Ramirez-Sierra Eric Churchill Anna D. Cunningham Andrey V. Malkovskiy Nancy A. Federspiel Fabio Cesar Gozzo Ana Claudia Torrecilhas Maria Julia Manso Alves Armando Jardim Ndao Momar Eric Dumonteil Daria Mochly-Rosen |
| author_sort |
Nir Qvit |
| title |
Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors |
| 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 |
| publisher |
Elsevier |
| series |
International Journal for Parasitology: Drugs and Drug Resistance |
| issn |
2211-3207 |
| publishDate |
2016-04-01 |
| description |
Parasitic diseases cause ∼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. Keywords: Chagas disease, Leishmaniasis, Peptide, LACK, TRACK, Scaffold protein |
| url |
http://www.sciencedirect.com/science/article/pii/S2211320716300100 |
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doaj-4cd893de292342dcb247cf36ee86cb222020-11-24T23:49:31ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072016-04-01617484Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitorsNir Qvit0Deborah Schechtman1Darlene Aparecida Pena2Denise Aparecida Berti3Chrislaine Oliveira Soares4Qianqian Miao5Liying (Annie) Liang6Lauren A. Baron7Christian Teh-Poot8Pedro Martínez-Vega9Maria Jesus Ramirez-Sierra10Eric Churchill11Anna D. Cunningham12Andrey V. Malkovskiy13Nancy A. Federspiel14Fabio Cesar Gozzo15Ana Claudia Torrecilhas16Maria Julia Manso Alves17Armando Jardim18Ndao Momar19Eric Dumonteil20Daria Mochly-Rosen21Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305, USA; Corresponding author.Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305, USA; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, SP, BrazilDepartamento de Bioquímica, Instituto de Química, Universidade de São Paulo, SP, BrazilDepartamento de Bioquímica, Instituto de Química, Universidade de São Paulo, SP, BrazilDepartamento de Bioquímica, Instituto de Química, Universidade de São Paulo, SP, BrazilNational Reference Centre for Parasitology, Research Institute of the McGill University, Montreal, CanadaNational Reference Centre for Parasitology, Research Institute of the McGill University, Montreal, CanadaLaboratorio de Parasitología, Centro de Investigaciones Regionales “Dr. Hideyo Noguchi”, Universidad Autónoma de Yucatán, Mérida, Yucatán, MexicoLaboratorio de Parasitología, Centro de Investigaciones Regionales “Dr. Hideyo Noguchi”, Universidad Autónoma de Yucatán, Mérida, Yucatán, MexicoLaboratorio de Parasitología, Centro de Investigaciones Regionales “Dr. Hideyo Noguchi”, Universidad Autónoma de Yucatán, Mérida, Yucatán, MexicoLaboratorio de Parasitología, Centro de Investigaciones Regionales “Dr. Hideyo Noguchi”, Universidad Autónoma de Yucatán, Mérida, Yucatán, MexicoDepartment of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305, USADepartment of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305, USABiomaterials and Advanced Drug Delivery Laboratory, Stanford University, Stanford, CA 94305, USADepartment of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305, USAInstitute of Chemistry, University of Campinas, Campinas, SP, BrazilDepartamento de Ciências Biológicas, Campus Diadema, UNIFESP, BrazilDepartamento de Bioquímica, Instituto de Química, Universidade de São Paulo, SP, BrazilInstitute of Parasitology and Centre for Host-Parasite Interactions, McGill University, Québec, CanadaNational Reference Centre for Parasitology, Research Institute of the McGill University, Montreal, CanadaLaboratorio de Parasitología, Centro de Investigaciones Regionales “Dr. Hideyo Noguchi”, Universidad Autónoma de Yucatán, Mérida, Yucatán, MexicoDepartment of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305, USAParasitic diseases cause ∼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. Keywords: Chagas disease, Leishmaniasis, Peptide, LACK, TRACK, Scaffold proteinhttp://www.sciencedirect.com/science/article/pii/S2211320716300100 |