High‐throughput screening and small animal models, where are we?

Abstract

Current high-throughput screening methods for drug discovery rely on the existence of targets. Moreover, most of the hits generated during screenings turn out to be invalid after further testing in animal models. To by-pass these limitations, efforts are now being made to screen chemical libraries on whole animals. One of the most commonly used animal model in biology is the murine model Mus musculus. However, its cost limit its use in large-scale therapeutic screening. In contrast, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the fish Danio rerio are gaining momentum as screening tools. These organisms combine genetic amenability, low cost and culture conditions that are compatible with large-scale screens. Their main advantage is to allow high-throughput screening in a whole-animal context. Moreover, their use is not dependent on the prior identification of a target and permits the selection of compounds with an improved safety profile. This review surveys the versatility of these animal models for drug discovery and discuss the options available at this day.

Levodopa-Induced Motor and Dopamine Receptor Changes in <b><i>Caenorhabditis elegans</i></b> Overexpressing Human Alpha-Synuclein

“…Several potential therapeutic strategies have been described [18] in current models of LID including increased coupling of striatal D1R to G protein Gαo, enhanced levels of adenylate cyclase and persistent anchoring of dopamine-bound D1R at membranes associated with a reduced expression of G-protein-coupled receptor kinases. High-throughput drug screening [19] in suitable preclinical animal models [20] of LID is a promising way to discover potential ‘hits' for such targets. Unfortunately translational research aimed at LID has been greatly limited by the lack of a preclinical model with quantifiable movement phenotypes which can be collected in a reproducible manner on a large scale.…”

Toxicity evaluation of boron nitride nanospheres and water-soluble boron nitride in <em>Caenorhabditis elegans</em>

“…14 As a sensitive and cost-efficient wholeanimal model with a short life cycle, C. elegans complements mammalian models [15][16][17][18] for assessing the toxicity of NMs at the organism or population level. [19][20][21] These NMs include metal nanoparticles (NPs; TiO 2 , Al 2 O 3 , and ZnO 2 ) [22][23][24] and carbon NPs (carbon NTs [CNTs], graphene oxide [GO], and graphite nanoplatelets).…”

Toxins and Drug Discovery

“…However, it may be possible to screen for novel activities using model organisms (such as nematodes (Caenorhabditis elegans) and zebrafish (Danio rerio) that have found some use in other drug discovery projects (Giacomotto and S egalat, 2010;Delvecchio et al, 2011;Asnani and Peterson, 2014;Bruni et al, 2014). Various zebrafish lines are available to allow effects on specific developmental and physiological process to be readily studied in transparent embryos in 96-well plates, and model systems for a wide range of human tumours are being developed in zebrafish (Mimeault and Batra, 2013).…”