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Home / Equine Research Bank / Int J Parasitol Drugs Drug Resist / High-throughput screen of drug repurposing library identifie...
International journal for parasitology. Drugs and drug resistance2018; 8(1); 137-144; doi: 10.1016/j.ijpddr.2018.02.002

High-throughput screen of drug repurposing library identifies inhibitors of Sarcocystis neurona growth.

Abstract: The apicomplexan parasite Sarcocystis neurona is the primary etiologic agent of equine protozoal myeloencephalitis (EPM), a serious neurologic disease of horses. Many horses in the U.S. are at risk of developing EPM; approximately 50% of all horses in the U.S. have been exposed to S. neurona and treatments for EPM are 60-70% effective. Advancement of treatment requires new technology to identify new drugs for EPM. To address this critical need, we developed, validated, and implemented a high-throughput screen to test 725 FDA-approved compounds from the NIH clinical collections library for anti-S. neurona activity. Our screen identified 18 compounds with confirmed inhibitory activity against S. neurona growth, including compounds active in the nM concentration range. Many identified inhibitory compounds have well-defined mechanisms of action, making them useful tools to study parasite biology in addition to being potential therapeutic agents. In comparing the activity of inhibitory compounds identified by our screen to that of other screens against other apicomplexan parasites, we found that most compounds (15/18; 83%) have activity against one or more related apicomplexans. Interestingly, nearly half (44%; 8/18) of the inhibitory compounds have reported activity against dopamine receptors. We also found that dantrolene, a compound already formulated for horses with a peak plasma concentration of 37.8 ± 12.8 ng/ml after 500 mg dose, inhibits S. neurona parasites at low concentrations (0.065 μM [0.036-0.12; 95% CI] or 21.9 ng/ml [12.1-40.3; 95% CI]). These studies demonstrate the use of a new tool for discovering new chemotherapeutic agents for EPM and potentially providing new reagents to elucidate biologic pathways required for successful S. neurona infection.
Copyright © 2018. Published by Elsevier Ltd.
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Publication Date: 2018-02-16 PubMed ID: 29547840PubMed Central: PMC6114104DOI: 10.1016/j.ijpddr.2018.02.002Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't
  • Validation Study

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study uses a large-scale screening methodology to identify potential new treatments for equine protozoal myeloencephalitis (EPM), by testing 725 FDA-approved compounds for their ability to inhibit the growth of Sarcocystis neurona, the parasite responsible for the disease.

Background

  • The study was prompted by the need for more effective treatments for equine protozoal myeloencephalitis (EPM), caused by the Sarcocystis neurona parasite. This neural disease presents a significant risk to many horses in the U.S., with current treatments showing only 60-70% effectiveness.
  • Identifying new drugs to treat EPM relied upon the development and validation of a high-throughput screening method, used to test a large number of compounds quickly.

Methods and Findings

  • The researchers tested 725 FDA-approved compounds from the NIH clinical collections library to identify any with anti-S. neurona activity.
  • The screening process found that 18 of the 725 compounds tested had verifiable inhibitory effects on S. neurona growth.
  • Many of these inhibitory compounds already have known modes of action, so they could be potential therapeutic treatments, as well as offer insight into parasite biology.
  • When comparing the effectiveness of these inhibiting compounds with those identified in other screens for different types of parasites within the Apicomplexa biological group, the majority (83%) showed activity against one or more of these related parasites.
  • The study found that nearly half of the inhibiting compounds had reported activity against dopamine receptors, a novel finding that could expand our understanding of disease mechanisms.
  • Notably, the compound dantrolene, which already has an established therapeutic use in horses, inhibited S. neurona at significantly low concentrations. Therefore, it represents a potential candidate for repurposing as an EPM treatment.

Implications and Conclusions

  • This research offers a new tool for exploring potential treatments for EPM. The high-throughput approach can help identify promising drugs more quickly than traditional testing methods.
  • The study additionally presents potential opportunities for further exploration of the biology of the S. neurona parasite, which could lead to new treatment routes.

Cite This Article

APA
Bowden GD, Land KM, O'Connor RM, Fritz HM. (2018). High-throughput screen of drug repurposing library identifies inhibitors of Sarcocystis neurona growth. Int J Parasitol Drugs Drug Resist, 8(1), 137-144. https://doi.org/10.1016/j.ijpddr.2018.02.002

Publication

International journal for parasitology. Drugs and drug resistance
ISSN: 2211-3207
NlmUniqueID: 101576715
Country: Netherlands
Language: English
Volume: 8
Issue: 1
Pages: 137-144

Researcher Affiliations

Bowden, Gregory D
  • Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA, USA.
Land, Kirkwood M
  • Department of Biological Sciences, University of the Pacific, Stockton, CA, USA.
O'Connor, Roberta M
  • Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA, USA. Electronic address: roboconnor@vetmed.wsu.edu.
Fritz, Heather M
  • Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA. Electronic address: hmfritz@ucdavis.edu.

MeSH Terms

  • Animals
  • Antiprotozoal Agents / chemistry
  • Antiprotozoal Agents / isolation & purification
  • Antiprotozoal Agents / pharmacology
  • Dantrolene / isolation & purification
  • Dantrolene / pharmacology
  • Drug Discovery / methods
  • Drug Repositioning
  • Encephalomyelitis / drug therapy
  • Encephalomyelitis / parasitology
  • High-Throughput Screening Assays
  • Horse Diseases / drug therapy
  • Horse Diseases / parasitology
  • Horses
  • Sarcocystis / drug effects
  • Sarcocystis / growth & development
  • Sarcocystosis / drug therapy
  • Sarcocystosis / parasitology
  • Sarcocystosis / veterinary
  • Small Molecule Libraries
  • United States
  • United States Food and Drug Administration

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