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High-throughput screening for selective appetite modulators: a multibehavioral and translational drug discovery strategy


Jordi, Josua; Guggiana-Nilo, Drago; Bolton, Andrew D; Prabha, Srishti; Ballotti, Kaitlyn; Herrera, Kristian; Rennekamp, Andrew J; Peterson, Randall T; Lutz, Thomas A; Engert, Florian (2018). High-throughput screening for selective appetite modulators: a multibehavioral and translational drug discovery strategy. Science Advances, 4(10):eaav1966.

Abstract

How appetite is modulated by physiological, contextual, or pharmacological influence is still unclear. Specifically, the discovery of appetite modulators is compromised by the abundance of side effects that usually limit in vivo drug action. We set out to identify neuroactive drugs that trigger only their intended single behavioral change, which would provide great therapeutic advantages. To identify these ideal bioactive small molecules, we quantified the impact of more than 10,000 compounds on an extended series of different larval zebrafish behaviors using an in vivo imaging strategy. Known appetite-modulating drugs altered feeding and a pleiotropy of behaviors. Using this multibehavioral strategy as an active filter for behavioral side effects, we identified previously unidentified compounds that selectively increased or reduced food intake by more than 50%. The general applicability of this strategy is shown by validation in mice. Mechanistically, most candidate compounds were independent of the main neurotransmitter systems. In addition, we identified compounds with multibehavioral impact, and correlational comparison of these profiles with those of known drugs allowed for the prediction of their mechanism of action. Our results illustrate an unbiased and translational drug discovery strategy for ideal psychoactive compounds and identified selective appetite modulators in two vertebrate species.

Abstract

How appetite is modulated by physiological, contextual, or pharmacological influence is still unclear. Specifically, the discovery of appetite modulators is compromised by the abundance of side effects that usually limit in vivo drug action. We set out to identify neuroactive drugs that trigger only their intended single behavioral change, which would provide great therapeutic advantages. To identify these ideal bioactive small molecules, we quantified the impact of more than 10,000 compounds on an extended series of different larval zebrafish behaviors using an in vivo imaging strategy. Known appetite-modulating drugs altered feeding and a pleiotropy of behaviors. Using this multibehavioral strategy as an active filter for behavioral side effects, we identified previously unidentified compounds that selectively increased or reduced food intake by more than 50%. The general applicability of this strategy is shown by validation in mice. Mechanistically, most candidate compounds were independent of the main neurotransmitter systems. In addition, we identified compounds with multibehavioral impact, and correlational comparison of these profiles with those of known drugs allowed for the prediction of their mechanism of action. Our results illustrate an unbiased and translational drug discovery strategy for ideal psychoactive compounds and identified selective appetite modulators in two vertebrate species.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:October 2018
Deposited On:02 Feb 2019 14:45
Last Modified:02 Feb 2019 21:07
Publisher:American Association for the Advancement of Science
ISSN:2375-2548
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1126/sciadv.aav1966
PubMed ID:30402545

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