A new in vivo screening paradigm to accelerate antimalarial drug discovery
| Autor: | Jose F. Garcia-Bustos, Santiago Ferrer, Didier Leroy, Esther Fernández, Javier Ibáñez, Noemí Magán-Marchal, Teresa Mulet, Leonard D. Shultz, María T. Fraile, Vanessa Gómez, María Belén Jiménez-Díaz, Francisco-Javier Gamo, Félix Calderón, Antonio Martinez, Lorena Cortés-Gil, Sara Viera, Iñigo Angulo-Barturen, David Matthew Wilson, Helen Garuti |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Time Factors
Mouse Plasmodium berghei Drug Evaluation Preclinical lcsh:Medicine Parasitemia Pharmacology Biochemistry Mice Drug Discovery lcsh:Science Multidisciplinary biology Drug discovery Statistics Animal Models Farmacia Plasmodium Falciparum Infectious Diseases Drug development Medicine Female Research Laboratories Research Article Drugs and Devices Drug Research and Development Medicina Science Policy Biostatistics Antimalarials Model Organisms In vivo parasitic diseases medicine Parasitic Diseases Animals Humans Biology Theoretical Biology Biología y Biomedicina lcsh:R Tropical Diseases (Non-Neglected) Plasmodium falciparum medicine.disease biology.organism_classification In vitro Malaria Immunology Feasibility Studies lcsh:Q Mathematics |
| Zdroj: | PLoS ONE, Vol 8, Iss 6, p e66967 (2013) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR), which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0) of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1) or induce parasite clearance (PRR >1) with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally) in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a feasible task. |
| Databáze: | OpenAIRE |
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