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.
Highlights
Malaria is a parasitic disease caused in humans by protozoa of the genus Plasmodium that invade and destroy red blood cells during their asexual multiplication
The potency of a compound is expressed as the ratio of P0 versus the parasitemia at the end of therapy (Figure 1B), which is equivalent to parasite reduction ratio (PRR)
Our results support the contention that the use of in vivo screening early in drug discovery can accelerate the process until compounds reach clinical trials
Summary
Malaria is a parasitic disease caused in humans by protozoa of the genus Plasmodium that invade and destroy red blood cells during their asexual multiplication. The disease continues to be a major burden to public health and economic development globally with an estimated 217 million malaria cases every year, resulting in about 0.7 million deaths [1]. Antimalarial drugs remain the mainstay for malaria treatment and control [3,4,5]. Artemisinin-based combination therapy (ACT) is recommended as first-line treatment for uncomplicated P. falciparum malaria [6], and its implementation has contributed significantly to reducing the malaria burden in many endemic countries and countering resistance to key antimalarial medicines [1,6]. The recent reports of artemisinin resistance in the Cambodia–Thai border [7,8,9], highlight the need for the continued development of new medicines [6,10]
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