Abstract
Biological organisms respond to environmental stressors by recruiting multiple cellular cascades that act to mitigate damage and ultimately enhance survival. This implies that compounds that interact with any of those pathways might improve organism's survival. Here, we report on an initial attempt to develop a drug screening assay based on the heat shock (HS) response of Caenorhabditis elegans nematodes. The protocol works by subjecting the worms to two HS conditions in the absence/presence of the test compounds. Post-heat shock survival is quantified manually or in semi-automatic manner by analyzing z-stack pictures. We blindly screened a cassette of 72 compounds in different developmental stages provided by Eli Lilly through their Open Innovation Drug Discovery program. The analysis indicated that, on average, therapeutically useful drugs increase survival to HS compared to compounds used in non-clinical settings. We developed a formalism that estimates the probability of a compound to enhance survival based on a comparison with a set of parameters calculated from a pool of 35 FDA-approved drugs. The method correctly identified the developmental stages of the Lilly compounds based on their relative abilities to enhance survival to the HS. Taken together these data provide proof of principle that an assay that measures the HS response of C. elegans can offer physiological and pharmacological insight in a cost- and time-efficient manner.
Highlights
Drug discovery is the main objective of the pharmaceutical industry
To address the boundaries of previous attempts to utilize C. elegans in drug discovery, we developed an assay based on the heat shock (HS) response [11,12,13]
To determine whether there is a relationship between survival to a heat shock (HS) response and therapeutic potential, we screened a pool of compounds provided to us by Eli Lilly through their Open Innovation Drug Discovery program
Summary
The development of a new drug begins in early stage assays that utilize in vitro models such as single-cells. These high-throughput screening assays are cost- and time-efficient but generally unable to recapitulate the complex physiology a compound is likely to encounter in a whole animal [1]. In vivo preclinical models are subsequently utilized to assess therapeutic potential and safety of selected candidates, but they are costly and time-consuming. For this reason, many potentially therapeutic molecules do not undergo additional evaluation [2].
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