Project description:To gain insight into the molecular mechanisms at work during progression through the pre-erythrocytic stages, a comparative microarray based transcriptional study was under taken on radiation attenuated (RAS) and wild type sporozoites (wtSPZ) as well as, and liver stage parasites collected 24 hours (24hrLS) and 48 hours (48hrLS) after wild type sporozoite infection. We were able to identify ~1100 genes significantly differentially expressed during one or more of the pre-erythrocytic stages relative to the mixed blood stages.
Project description:Most malaria drug development focuses on parasite stages detected in red-blood cells even though to achieve eradication next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4,000 commercially available compounds with previously demonstrated blood stage activity (IC50 < 1 µM), and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. Our orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 mg/kg) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.
Project description:To gain insight into the molecular mechanisms at work during progression through the pre-erythrocytic stages, a comparative microarray based transcriptional study was under taken on radiation attenuated (RAS) and wild type sporozoites (wtSPZ) as well as, and liver stage parasites collected 24 hours (24hrLS) and 48 hours (48hrLS) after wild type sporozoite infection. We were able to identify ~1100 genes significantly differentially expressed during one or more of the pre-erythrocytic stages relative to the mixed blood stages. This study compared the gene expression profiles of radiation attenuated sporozoites (RAS), wild type sporooites (wtSPZ), and infected hepatocytes collected 24hr (24hrLS) and 48hr (48hrLS) after sporozoite infection, using a common reference design. Each sample was hybridized with an equal amount of reference RNA. 48hrLS: 4 biological replicates, with 2 total technical replicates and one dye swap; 24hrLS: 4 biologicla replicates, with 3 total technical replicates; RAS: 2 biological replicates, with 2 technical replicates total, and two tota dye swaps; wtSPZ: 2 biological replicates, with 2 total technical replicates and 2 total dye swaps
