RESUMEN
Parasitic diseases cause â¼ 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.
Asunto(s)
Leishmania/efectos de los fármacos , Péptidos/síntesis química , Péptidos/farmacología , Proteínas Protozoarias/antagonistas & inhibidores , Receptores de Superficie Celular/antagonistas & inhibidores , Tripanocidas/farmacología , Trypanosoma/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Antígenos de Protozoos/química , Diseño de Fármacos , Leishmania/química , Leishmania/genética , Leishmaniasis/tratamiento farmacológico , Leishmaniasis/parasitología , Ratones , Parasitemia/tratamiento farmacológico , Péptidos/administración & dosificación , Proteínas Protozoarias/química , Receptores de Cinasa C Activada , Receptores de Superficie Celular/química , Alineación de Secuencia , Tripanocidas/administración & dosificación , Tripanocidas/química , Trypanosoma/genética , Tripanosomiasis/tratamiento farmacológico , Tripanosomiasis/parasitologíaRESUMEN
We present the diploid genome sequence of the fungal pathogen Candida albicans. Because C. albicans has no known haploid or homozygous form, sequencing was performed as a whole-genome shotgun of the heterozygous diploid genome in strain SC5314, a clinical isolate that is the parent of strains widely used for molecular analysis. We developed computational methods to assemble a diploid genome sequence in good agreement with available physical mapping data. We provide a whole-genome description of heterozygosity in the organism. Comparative genomic analyses provide important clues about the evolution of the species and its mechanisms of pathogenesis.