title: A new in vivo screening paradigm to accelerate antimalarial drug discovery.
abstract: 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.
authors.affiliation: Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
authors.forename: María Belén
authors.initials: MB
authors.lastname: Jiménez-Díaz
authors.forename: Sara
authors.initials: S
authors.lastname: Viera
authors.forename: Javier
authors.initials: J
authors.lastname: Ibáñez
authors.forename: Teresa
authors.initials: T
authors.lastname: Mulet
authors.forename: Noemí
authors.initials: N
authors.lastname: Magán-Marchal
authors.forename: Helen
authors.initials: H
authors.lastname: Garuti
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gómez
authors.forename: Lorena
authors.initials: L
authors.lastname: Cortés-Gil
authors.forename: Antonio
authors.initials: A
authors.lastname: Martínez
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Fraile
authors.forename: Félix
authors.initials: F
authors.lastname: Calderón
authors.forename: Esther
authors.initials: E
authors.lastname: Fernández
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: Didier
authors.initials: D
authors.lastname: Leroy
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.forename: José Francisco
authors.initials: JF
authors.lastname: García-Bustos
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Gamo
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008288:Malaria / Q000150:complications / Q000188:drug therapy; D051379:Mice; D018512:Parasitemia / Q000150:complications; D010962:Plasmodium berghei / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
chemical_list: D000962:Antimalarials