Chemical screening in zebrafish for novel biological and therapeutic discovery

Abstract

Zebrafish chemical screening allows for an in vivo assessment of small molecule modulation of biological processes. Compound toxicities, chemical alterations by metabolism, pharmacokinetic and pharmacodynamic properties, and modulation of cell niches can be studied with this method. Furthermore, zebrafish screening is straightforward and cost effective. Zebrafish provide an invaluable platform for novel therapeutic discovery through chemical screening.

Introduction

In the past 15 years, many successful therapeutics have been efficiently discovered by cell-based and biochemical drug screening. However, these screening methods do not consider in vivo small molecule activity. Potential therapeutics from such screens often do not pass in vivo testing in live organisms such as mice, since they have inherent toxicity and poor pharmacoproperties undetectable by the screening process. Also, small molecules may act differently in whole organisms due to their complex biology, as compared to more straightforward biology in cell cultures and purified proteins. Such screens are encountering problems with proteins that are difficult to target, such as transcription factors. These proteins are termed “undruggable”, since they are inept in binding small molecules and often carry out their functions through protein–protein or protein–DNA/RNA interactions.

Zebrafish chemical screening can address the problems inherent in cell-based and biochemical screens. Screening in a whole organism context means drug toxicity and in vivo drug effects are addressed concurrently. Whole organism screening has the advantage of being less targeted then cell-based and biochemical screens, allowing the drug to interact with any biological pathway. The readout is an alteration of a whole organism phenotype that relates well to disease. In contrast, protein–compound binding or cell-based reporters give little indication of disease phenotype modulation. Furthermore, technological advances have made zebrafish screens straightforward and cost effective. It has been 15 years since the first zebrafish screen was attempted, and already, a number of potential therapeutics have been discovered that target processes ranging from hematopoiesis to cancer (Table 1). Zebrafish screening might also provide the ability to discover therapeutic modulators of “undruggable” processes, as it explores biology to a complexity unseen in cell-based or biochemical screens. Overall, zebrafish screening is a convenient and ideal technology for novel therapeutic discovery.