Mar 2, 2011

Identification of small molecule lead compounds for visceral leishmaniasis using a novel ex vivo splenic explant model system

PLoS Neglected Tropical Diseases
Yaneth OsorioP C Melby

Abstract

New drugs are needed to treat visceral leishmaniasis (VL) because the current therapies are toxic, expensive, and parasite resistance may weaken drug efficacy. We established a novel ex vivo splenic explant culture system from hamsters infected with luciferase-transfected Leishmania donovani to screen chemical compounds for anti-leishmanial activity. THIS MODEL HAS ADVANTAGES OVER IN VITRO SYSTEMS IN THAT IT: 1) includes the whole cellular population involved in the host-parasite interaction; 2) is initiated at a stage of infection when the immunosuppressive mechanisms that lead to progressive VL are evident; 3) involves the intracellular form of Leishmania; 4) supports parasite replication that can be easily quantified by detection of parasite-expressed luciferase; 5) is adaptable to a high-throughput screening format; and 6) can be used to identify compounds that have both direct and indirect anti-parasitic activity. The assay showed excellent discrimination between positive (amphotericin B) and negative (vehicle) controls with a Z' Factor >0.8. A duplicate screen of 4 chemical libraries containing 4,035 compounds identified 202 hits (5.0%) with a Z score of <-1.96 (p<0.05). Eighty-four (2.1%) of the hits were classified as l...Continue Reading

Mentioned in this Paper

Trientine
Pathologic Cytolysis
Metabolic Process, Cellular
Macrophages, Peritoneal
Mesocricetus auratus
Dione
Immune Response
Monoclonal antibodies, antineoplastic
Flow Cytometry
Plant alkaloid

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