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.

Model-Informed Drug Development for Malaria Therapeutics

“…Researchers have investigated the potential of the SCID huMouse model to translate estimated critical parameters to those observed in clinical trials (8). Recent studies demonstrated a poor correlation between parasite clearance rates (in vivo parasite reduction ratios) derived from mouse models and those reported from patients with malaria (8); this result is consistent with previous observations (27). However, the estimation of the IC 50 from the SCID huMouse model has yielded promising results as a surrogate of IC 50 in humans (8).…”

In Vivo Antimalarial Activity and Mechanisms of Action of 4-Nerolidylcatechol Derivatives

“…The development of derivatives of 1 exhibiting greater in vivo antimalarial activity would therefore be desirable. In this vein, it is important to keep in mind the possible limitations [46] and slow clearance [47]) and artemisinin derivatives, exemplified by artesunate (recrudescence below 80 mg kg Ϫ1 day Ϫ1 via oral against P. vinckei) (48) are not optimal for treating rodent malaria parasites but are of unquestionable therapeutic value in humans.…”

A synthetic cGMP-sensitive gene switch providing Viagra®-controlled gene expression in mammalian cells and mice

“…Cell-based screening assays and early validation in animals provide multiple endpoints such as intracellular target specificity, cytotoxicity, bioavailability, pharmacokinetics and efficacy in a physiological context. Integrative information on safety and efficacy may facilitate the drug development process, and various cell-based proof-of-concept screening assays (Aubel et al, 2001;Gonzalez-Nicolini et al, 2004;Kim et al, 2015;Weber et al, 2008) and screening studies in animals (Higuera et al, 2013;Jimenez-Diaz et al, 2013;MacRae, 2013;Varble et al, 2013) have shown encouraging results.…”