Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors

Nir Qvit; Deborah Schechtman; Darlene Aparecida Pena; Denise Aparecida Berti; Chrislaine Oliveira Soares; Qianqian Miao; Liying 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

doi:10.1016/j.ijpddr.2016.02.003

Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors

Nir Qvit, Deborah Schechtman, Darlene Aparecida Pena, Denise Aparecida Berti, Chrislaine Oliveira Soares, Qianqian Miao, Liying 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 MomarEric Dumonteil, Daria Mochly-Rosen

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	74-84
Number of pages	11
Journal	International Journal for Parasitology: Drugs and Drug Resistance
Volume	6
Issue number	1
DOIs	https://doi.org/10.1016/j.ijpddr.2016.02.003
State	Published - 1 Apr 2016
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2016 The Authors.

Funding

This work was supported by the National Institutes of Health ( TW008781-01C-IDEA and SPARK to NQ) and ( AI078505 to DM-R). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors declare that there are no conflicts of interest. We thank Dr. Ben Kelly from Louisiana State University for providing antibodies. We thank Dr. Silvia RB Uliana from The University of São Paulo for carrying out initial studies.

Funders	Funder number
National Institutes of Health	TW008781-01C-IDEA, AI078505
National Heart, Lung, and Blood Institute	R01HL052141

Keywords

Chagas disease
LACK
Leishmaniasis
Peptide
Scaffold protein
TRACK

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ijpddr.2016.02.003

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Qvit, N., Schechtman, D., Pena, D. A., Berti, D. A., Soares, C. O., Miao, Q., Liang, L., Baron, L. A., Teh-Poot, C., Martínez-Vega, P., Ramirez-Sierra, M. J., Churchill, E., Cunningham, A. D., Malkovskiy, A. V., Federspiel, N. A., Gozzo, F. C., Torrecilhas, A. C., Manso Alves, M. J., Jardim, A., ... Mochly-Rosen, D. (2016). Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors. International Journal for Parasitology: Drugs and Drug Resistance, 6(1), 74-84. https://doi.org/10.1016/j.ijpddr.2016.02.003

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Qvit, N, Schechtman, D, Pena, DA, Berti, DA, Soares, CO, Miao, Q, Liang, L, Baron, LA, Teh-Poot, C, Martínez-Vega, P, Ramirez-Sierra, MJ, Churchill, E, Cunningham, AD, Malkovskiy, AV, Federspiel, NA, Gozzo, FC, Torrecilhas, AC, Manso Alves, MJ, Jardim, A, Momar, N, Dumonteil, E & Mochly-Rosen, D 2016, 'Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors', International Journal for Parasitology: Drugs and Drug Resistance, vol. 6, no. 1, pp. 74-84. https://doi.org/10.1016/j.ijpddr.2016.02.003

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AU - Qvit, Nir

AU - Schechtman, Deborah

AU - Pena, Darlene Aparecida

AU - Berti, Denise Aparecida

AU - Soares, Chrislaine Oliveira

AU - Miao, Qianqian

AU - Liang, Liying

AU - Baron, Lauren A.

AU - Teh-Poot, Christian

AU - Martínez-Vega, Pedro

AU - Ramirez-Sierra, Maria Jesus

AU - Churchill, Eric

AU - Cunningham, Anna D.

AU - Malkovskiy, Andrey V.

AU - Federspiel, Nancy A.

AU - Gozzo, Fabio Cesar

AU - Torrecilhas, Ana Claudia

AU - Manso Alves, Maria Julia

AU - Jardim, Armando

AU - Momar, Ndao

AU - Dumonteil, Eric

AU - Mochly-Rosen, Daria

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Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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