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

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

Author Qvit, Nir Google Scholar
Schechtman, Deborah Google Scholar
Pena, Darlene Aparecida Google Scholar
Berti, Denise Aparecida Google Scholar
Soares, Chrislaine Oliveira Google Scholar
Miao, Qianqian Google Scholar
Liang, Liying (Annie) Google Scholar
Baron, Lauren A. Google Scholar
Teh-Poot, Christian Google Scholar
Martinez-Vega, Pedro Google Scholar
Ramirez-Sierra, Maria Jesus Google Scholar
Churchill, Eric Google Scholar
Cunningham, Anna D. Google Scholar
Malkovskiy, Andrey V. Google Scholar
Federspiel, Nancy A. Google Scholar
Gozzo, Fabio Cesar Google Scholar
Torrecilhas, Ana Claudia Autor UNIFESP Google Scholar
Manso Alves, Maria Julia Google Scholar
Jardim, Armando Google Scholar
Momar, Ndao Google Scholar
Dumonteil, Eric Google Scholar
Mochly-Rosen, Daria Google Scholar
Abstract 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.
Keywords Chagas disease
Leishmaniasis
Peptide
LACK
TRACK
Scaffold protein
xmlui.dri2xhtml.METS-1.0.item-coverage Oxford
Language English
Sponsor National Institutes of Health
Grant number NIH: TW008781-01C-IDEA
NIH: AI078505
Date 2016
Published in International Journal For Parasitology-Drugs And Drug Resistance. Oxford, v. 6, n. 1, p. 74-84, 2016.
ISSN 2211-3207 (Sherpa/Romeo, impact factor)
Publisher Elsevier Sci Ltd
Extent 74-84
Origin http://dx.doi.org/10.1016/j.ijpddr.2016.02.003
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000372717200008
URI https://repositorio.unifesp.br/handle/11600/56191

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