title: Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors.
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.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305, USA. Electronic address: nirqvit@stanford.edu.
authors.forename: Nir
authors.initials: N
authors.lastname: Qvit
authors.affiliation: 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, Brazil.
authors.forename: Deborah
authors.initials: D
authors.lastname: Schechtman
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, SP, Brazil.
authors.forename: Darlene Aparecida
authors.initials: DA
authors.lastname: Pena
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, SP, Brazil.
authors.forename: Denise Aparecida
authors.initials: DA
authors.lastname: Berti
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, SP, Brazil.
authors.forename: Chrislaine Oliveira
authors.initials: CO
authors.lastname: Soares
authors.affiliation: National Reference Centre for Parasitology, Research Institute of the McGill University, Montreal, Canada.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Miao
authors.affiliation: National Reference Centre for Parasitology, Research Institute of the McGill University, Montreal, Canada.
authors.forename: Liying Annie
authors.initials: LA
authors.lastname: Liang
authors.affiliation: Laboratorio de Parasitología, Centro de Investigaciones Regionales "Dr. Hideyo Noguchi", Universidad Autónoma de Yucatán, Mérida, Yucatán, Mexico.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Baron
authors.affiliation: Laboratorio de Parasitología, Centro de Investigaciones Regionales "Dr. Hideyo Noguchi", Universidad Autónoma de Yucatán, Mérida, Yucatán, Mexico.
authors.forename: Christian
authors.initials: C
authors.lastname: Teh-Poot
authors.affiliation: Laboratorio de Parasitología, Centro de Investigaciones Regionales "Dr. Hideyo Noguchi", Universidad Autónoma de Yucatán, Mérida, Yucatán, Mexico.
authors.forename: Pedro
authors.initials: P
authors.lastname: Martínez-Vega
authors.affiliation: Laboratorio de Parasitología, Centro de Investigaciones Regionales "Dr. Hideyo Noguchi", Universidad Autónoma de Yucatán, Mérida, Yucatán, Mexico.
authors.forename: Maria Jesus
authors.initials: MJ
authors.lastname: Ramirez-Sierra
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Churchill
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305, USA.
authors.forename: Anna D
authors.initials: AD
authors.lastname: Cunningham
authors.affiliation: Biomaterials and Advanced Drug Delivery Laboratory, Stanford University, Stanford, CA 94305, USA.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Malkovskiy
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305, USA.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Federspiel
authors.affiliation: Institute of Chemistry, University of Campinas, Campinas, SP, Brazil.
authors.forename: Fabio Cesar
authors.initials: FC
authors.lastname: Gozzo
authors.affiliation: Departamento de Ciências Biológicas, Campus Diadema, UNIFESP, Brazil.
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Torrecilhas
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, SP, Brazil.
authors.forename: Maria Julia
authors.initials: MJ
authors.lastname: Manso Alves
authors.affiliation: Institute of Parasitology and Centre for Host-Parasite Interactions, McGill University, Québec, Canada.
authors.forename: Armando
authors.initials: A
authors.lastname: Jardim
authors.affiliation: National Reference Centre for Parasitology, Research Institute of the McGill University, Montreal, Canada.
authors.forename: Ndao
authors.initials: N
authors.lastname: Momar
authors.affiliation: Laboratorio de Parasitología, Centro de Investigaciones Regionales "Dr. Hideyo Noguchi", Universidad Autónoma de Yucatán, Mérida, Yucatán, Mexico.
authors.forename: Eric
authors.initials: E
authors.lastname: Dumonteil
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305, USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000953:Antigens, Protozoan / Q000737:chemistry; D015195:Drug Design; D007891:Leishmania / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D007896:Leishmaniasis / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D018512:Parasitemia / Q000188:drug therapy; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016415:Sequence Alignment; D014344:Trypanocidal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D014345:Trypanosoma / Q000187:drug effects* / Q000235:genetics; D014352:Trypanosomiasis / Q000188:drug therapy / Q000469:parasitology
chemical_list: D000953:Antigens, Protozoan; D010455:Peptides; D015800:Protozoan Proteins; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D014344:Trypanocidal Agents; C093139:LACK antigen, Leishmania
keywords: Chagas disease; LACK; Leishmaniasis; Peptide; Scaffold protein; TRACK