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

• Published in: International journal for parasitology -- drugs and drug resistance 2016-04, Vol.6 (1), p.74-84
• Main Authors: Qvit, Nir, Schechtman, Deborah, Pena, Darlene Aparecida, Berti, Denise Aparecida, Soares, Chrislaine Oliveira, Miao, Qianqian, Liang, Liying (Annie), Baron, Lauren A., Teh-Poot, Christian, Martínez-Vega, Pedro, Ramirez-Sierra, Maria Jesus, Churchill, Eric, Cunningham, Anna D., Malkovskiy, Andrey V., Federspiel, Nancy A., Gozzo, Fabio Cesar, Torrecilhas, Ana Claudia, Manso Alves, Maria Julia, Jardim, Armando, Momar, Ndao, Dumonteil, Eric, Mochly-Rosen, Daria
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antigens, Protozoan - chemistry; Chagas disease; Drug Design; LACK; Leishmania - chemistry; Leishmania - drug effects; Leishmania - genetics; Leishmaniasis; Leishmaniasis - drug therapy; Leishmaniasis - parasitology; Mice; Parasitemia - drug therapy; Peptide; Peptides - administration & dosage; Peptides - chemical synthesis; Peptides - pharmacology; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - chemistry; Receptors for Activated C Kinase; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - chemistry; Scaffold protein; Sequence Alignment; TRACK; Trypanocidal Agents - administration & dosage; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma - drug effects; Trypanosoma - genetics; Trypanosomiasis - drug therapy; Trypanosomiasis - parasitology
• ISSN: 2211-3207; 2211-3207
• DOI: 10.1016/j.ijpddr.2016.02.003

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 (Trypanosomareceptor 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. [Display omitted] •Identified unique short sequences conserved in parasite but not in host orthologue.•Peptides corresponding to these sequences are active anti-parasitic drug lead.•Cyclization of the peptides generates drug leads for in vivo proof of concept.