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Veterinary parasitology2018; 251; 90-94; doi: 10.1016/j.vetpar.2017.12.024

In vitro growth inhibition of Theileria equi by bumped kinase inhibitors.

Abstract: Theileria equi, an etiologic agent of equine piroplasmosis, is a tick-transmitted hemoprotozoan of the phylum Apicomplexa. Recent outbreaks of piroplasmosis in the United States have renewed interest in safe and effective treatment options. Although imidocarb dipropionate (IMD) is the drug of choice for clearance of T. equi, adverse reactions and recently documented resistance support the need for alternative therapeutic strategies. The recently described bumped kinase inhibitors (BKIs) are a new class of compounds that could potentially be used as safe and effective alternatives to IMD. In an initial effort to evaluate this potential, herein we determined the T. equi growth inhibitory activity of 11 BKIs relative to that of IMD and the previously tested BKI 1294. Because some BKIs have known human ether-à-go-go related gene (hERG) channel activity, we also assessed the hERG activity of each compound with the goal to identify those with the highest potency against T. equi coupled with the lowest potential for cardiotoxicity. Results: Six BKIs inhibited T. equi growth in vitro, including the previously evaluated BKI 1294 which was used as a positive control. All six compounds were significantly less potent (higher 50% effective concentration (EC)) than IMD. Two of those compounds were more potent than BKI 1294 control but had similar hERG activity. Although the remaining three compounds had similar to lower potency than BKI 1294, hERG EC was higher for three of them (BKI 1735, BKI 1369 and BKI 1318). Conclusions: The BKI compounds evaluated in this study inhibited T. equi in vitro and had diverse hERG activity. Based on these considerations, three compounds would be suitable for further evaluation. While these results provide a foundation for future work, in vivo pharmacokinetic, pharmacodynamics, and safety studies are needed before BKI compounds can be recommended for clinical use in T. equi infected horses.
Copyright © 2018 Elsevier B.V. All rights reserved.
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Publication Date: 2018-01-01 PubMed ID: 29426483PubMed Central: PMC5959018DOI: 10.1016/j.vetpar.2017.12.024Google Scholar: Lookup
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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 investigates the effectiveness of a new class of compounds called bumped kinase inhibitors (BKIs) in inhibiting the growth of Theileria equi, a parasite that causes equine piroplasmosis. The research identified six BKIs which inhibited T. equi’s growth in vitro, though their effectiveness was less than the current treatment of choice, imidocarb dipropionate. Researchers further compared these BKIs to evaluate their potential cardiotoxicity, leading them to identify three as safe for further study.

Introduction to Theileria equi and the Need for New Treatment Options

  • The equine parasite Theileria equi is responsible for the disease equine piroplasmosis, which is transmitted by ticks.
  • Due to recent outbreaks in the United States, there’s an increased interest in finding safe and effective treatment options.
  • The drug currently used for treatment is imidocarb dipropionate (IMD). However, documented resistance and adverse reactions present a need for alternatives.

Bumped Kinase Inhibitors

  • The bumped kinase inhibitors (BKIs) are a new class of drugs that might be used as an alternative to IMD.
  • The study examines the effectiveness of 11 BKIs by comparing their ability to inhibit T. equi growth to IMD and a previously tested BKI.
  • The potential cardiotoxicity of the BKIs was assessed by evaluating their human ether-à-go-go related gene (hERG) channel activity.

Results

  • Six of the 11 BKIs tested inhibited T. equi growth in vitro, including the BKI used as a control group.
  • All six were less potent than IMD, implying they required higher concentrations to be effective.
  • Three BKIs showed similar to lower potency but higher hERG activity than the control BKI. High hERG activity indicates a potential risk of cardiotoxicity.

Conclusion and Further Steps

  • The study concludes that three BKI compounds could be suitable for further evaluation, as they showed potency against T. equi and acceptable hERG activity levels.
  • Before recommending these compounds for clinical use, the authors advise conducting further studies to assess factors such as pharmacokinetics, pharmacodynamics, and safety in vivo.

Cite This Article

APA
Gimenez F, Hines SA, Evanoff R, Ojo KK, Van Voorhis WC, Maly DJ, Vidadala RSR, Mealey RH. (2018). In vitro growth inhibition of Theileria equi by bumped kinase inhibitors. Vet Parasitol, 251, 90-94. https://doi.org/10.1016/j.vetpar.2017.12.024

Publication

Veterinary parasitology
ISSN: 1873-2550
NlmUniqueID: 7602745
Country: Netherlands
Language: English
Volume: 251
Pages: 90-94
PII: S0304-4017(17)30536-8

Researcher Affiliations

Gimenez, Fernanda
  • Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA, 99164, USA. Electronic address: fgimenez@vetmed.wsu.edu.
Hines, Siddra A
  • Veterinary Research and Development, Inc., Pullman, WA, 99163, USA.
Evanoff, Ryan
  • Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA, 99164, USA.
Ojo, Kayode K
  • Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington, Seattle, WA, 98109, USA.
Van Voorhis, Wesley C
  • Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington, Seattle, WA, 98109, USA; Department of Global Health, University of Washington, Seattle, WA, 98195, USA.
Maly, Dustin J
  • Department of Chemistry, University of Washington, Seattle, WA, 98195, USA; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
Vidadala, Rama S R
  • Department of Chemistry, University of Washington, Seattle, WA, 98195, USA.
Mealey, Robert H
  • Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA, 99164, USA.

MeSH Terms

  • Animals
  • Antiprotozoal Agents / pharmacology
  • Antiprotozoal Agents / therapeutic use
  • Babesiosis / drug therapy
  • Babesiosis / parasitology
  • Cattle
  • Horse Diseases / drug therapy
  • Horse Diseases / parasitology
  • Horses / parasitology
  • Humans
  • Imidocarb / analogs & derivatives
  • Imidocarb / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Theileria / drug effects
  • Theileria / growth & development
  • Theileriasis / drug therapy
  • Theileriasis / epidemiology

Grant Funding

  • R01 AI089441 / NIAID NIH HHS
  • R01 AI111341 / NIAID NIH HHS
  • R01 HD080670 / NICHD NIH HHS

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Citations

This article has been cited 3 times.
  1. Onzere CK, Hulbert M, Sears KP, Williams LBA, Fry LM. Tulathromycin and Diclazuril Lack Efficacy against Theileria haneyi, but Tulathromycin Is Not Associated with Adverse Clinical Effects in Six Treated Adult Horses. Pathogens 2023 Mar 14;12(3).
    doi: 10.3390/pathogens12030453pubmed: 36986375google scholar: lookup
  2. Sears K, Knowles D, Dinkel K, Mshelia PW, Onzere C, Silva M, Fry L. Imidocarb Dipropionate Lacks Efficacy against Theileria haneyi and Fails to Consistently Clear Theileria equi in Horses Co-Infected with T. haneyi. Pathogens 2020 Dec 10;9(12).
    doi: 10.3390/pathogens9121035pubmed: 33321715google scholar: lookup
  3. Tirosh-Levy S, Gottlieb Y, Fry LM, Knowles DP, Steinman A. Twenty Years of Equine Piroplasmosis Research: Global Distribution, Molecular Diagnosis, and Phylogeny. Pathogens 2020 Nov 8;9(11).
    doi: 10.3390/pathogens9110926pubmed: 33171698google scholar: lookup
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