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Home / Equine Research Bank / Int J Parasitol / Selective inhibition of Sarcocystis neurona calcium-dependen...
International journal for parasitology2016; 46(13-14); 871-880; doi: 10.1016/j.ijpara.2016.08.003

Selective inhibition of Sarcocystis neurona calcium-dependent protein kinase 1 for equine protozoal myeloencephalitis therapy.

Abstract: Sarcocystis neurona is the most frequent cause of equine protozoal myeloencephalitis, a debilitating neurological disease of horses that can be difficult to treat. We identified SnCDPK1, the S. neurona homologue of calcium-dependent protein kinase 1 (CDPK1), a validated drug target in Toxoplasma gondii. SnCDPK1 shares the glycine "gatekeeper" residue of the well-characterized T. gondii enzyme, which allows the latter to be targeted by bumped kinase inhibitors. This study presents detailed molecular and phenotypic evidence that SnCDPK1 can be targeted for rational drug development. Recombinant SnCDPK1 was tested against four bumped kinase inhibitors shown to potently inhibit both T. gondii (Tg) CDPK1 and T. gondii tachyzoite growth. SnCDPK1 was inhibited by low nanomolar concentrations of these BKIs and S. neurona growth was inhibited at 40-120nM concentrations. Thermal shift assays confirmed these bumped kinase inhibitors bind CDPK1 in S. neurona cell lysates. Treatment with bumped kinase inhibitors before or after invasion suggests that bumped kinase inhibitors interfere with S. neurona mammalian host cell invasion in the 0.5-2.5μM range but interfere with intracellular division at 2.5μM. In vivo proof-of-concept experiments were performed in a murine model of S. neurona infection. The experimental infected groups treated for 30days with compound BKI-1553 (n=10 mice) had no signs of disease, while the infected control group had severe signs and symptoms of infection. Elevated antibody responses were found in 100% of control infected animals, but only 20% of BKI-1553 treated infected animals. Parasites were found in brain tissues of 100% of the control infected animals, but only in 10% of the BKI-1553 treated animals. The bumped kinase inhibitors used in these assays have been chemically optimized for potency, selectivity and pharmacokinetic properties, and hence are good candidates for treatment of equine protozoal myeloencephalitis.
Copyright © 2016 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.
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Publication Date: 2016-10-08 PubMed ID: 27729271PubMed Central: PMC5130624DOI: 10.1016/j.ijpara.2016.08.003Google 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.

The research article is about the identification of a protein in Sarcocystis neurona, a parasite that causes equine protozoal myeloencephalitis (EPM), a debilitating disease in horses. The researchers evaluated the efficacy of selective inhibitors of this protein, suggesting that these substances could be a new treatment approach for EPM.

Objective of the Study

  • The aim of this study was to identify SnCDPK1, a homologue of calcium-dependent protein kinase 1 (CDPK1) in Sarcocystis neurona – a parasite that causes equine protozoal myeloencephalitis, a devastating neurological disease in horses. The researchers wanted to assess whether selective SnCDPK1 inhibitors could potentially treat EPM.

Methods and Procedures

  • Four bumped kinase inhibitors were tested against recombinant SnCDPK1, these inhibitors were previously shown to efficiently inhibit T. gondii CDPK1 and T. gondii tachyzoite growth.
  • The researchers used thermal shift assays to confirm SnCDPK1 binding.
  • In vivo experiments were conducted using a murine model of S. neurona. Mice were divided into groups and treated with BKI-1553 for 30 days.

Findings of the Study

  • They found SnCDPK1 to be inhibited by low nanomolar concentrations of bumped kinase inhibitors.
  • Mammalian cells infected with S. neurona showed disruption of the host cell invasion process in the 0.5-2.5μM range of bumped kinase inhibitors. High concentrations of inhibitors (2.5μM) interfered with intracellular division of S. neurona.
  • In the in vivo model, mice that were treated for 30 days with the bumped kinase inhibitor BKI-1553 did not show signs of the disease.
  • Antibodies were found in all control (untreated) infected animals whereas only 20% of infected animals treated with BKI-1553 had elevated antibody responses. Also, parasites were found in brains of 100% of control infected animals, but only in 10% of treated animals.

Conclusion of the Study

  • Based on the results, the researchers concluded that targeting SnCDPK1 with bumped kinase inhibitors could be a promising therapeutic approach for treating equine protozoal myeloencephalitis.

Cite This Article

APA
Ojo KK, Dangoudoubiyam S, Verma SK, Scheele S, DeRocher AE, Yeargan M, Choi R, Smith TR, Rivas KL, Hulverson MA, Barrett LK, Fan E, Maly DJ, Parsons M, Dubey JP, Howe DK, Van Voorhis WC. (2016). Selective inhibition of Sarcocystis neurona calcium-dependent protein kinase 1 for equine protozoal myeloencephalitis therapy. Int J Parasitol, 46(13-14), 871-880. https://doi.org/10.1016/j.ijpara.2016.08.003

Publication

International journal for parasitology
ISSN: 1879-0135
NlmUniqueID: 0314024
Country: England
Language: English
Volume: 46
Issue: 13-14
Pages: 871-880
PII: S0020-7519(16)30211-9

Researcher Affiliations

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. Electronic address: ojo67kk@u.washington.edu.
Dangoudoubiyam, Sriveny
  • Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
Verma, Shiv K
  • United States Department of Agriculture, Agricultural Research Service, Beltsville Agricultural Research Center, Animal Parasitic Diseases Laboratory, Beltsville, MD 20705, USA.
Scheele, Suzanne
  • Center for Infectious Disease Research, Seattle, WA 98109, USA.
DeRocher, Amy E
  • Center for Infectious Disease Research, Seattle, WA 98109, USA.
Yeargan, Michelle
  • Department of Veterinary Science, University of Kentucky, Lexington, KY 40546, USA.
Choi, Ryan
  • Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington, Seattle, WA 98109, USA.
Smith, Tess R
  • Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington, Seattle, WA 98109, USA.
Rivas, Kasey L
  • Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington, Seattle, WA 98109, USA.
Hulverson, Matthew A
  • Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington, Seattle, WA 98109, USA.
Barrett, Lynn 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.
Fan, Erkang
  • Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Maly, Dustin J
  • Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
Parsons, Marilyn
  • Center for Infectious Disease Research, Seattle, WA 98109, USA; Department of Global Health, University of Washington, Seattle, WA 98195, USA.
Dubey, Jitender P
  • United States Department of Agriculture, Agricultural Research Service, Beltsville Agricultural Research Center, Animal Parasitic Diseases Laboratory, Beltsville, MD 20705, USA.
Howe, Daniel K
  • Department of Veterinary Science, University of Kentucky, Lexington, KY 40546, USA. Electronic address: daniel.howe@uky.edu.
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. Electronic address: wesley@uw.edu.

MeSH Terms

  • Animals
  • Cell Line
  • Chlorocebus aethiops
  • Encephalomyelitis / drug therapy
  • Encephalomyelitis / parasitology
  • Female
  • Horse Diseases / drug therapy
  • Horse Diseases / parasitology
  • Horses
  • Interferon-gamma / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Kinases / drug effects
  • Rabbits
  • Sarcocystis / drug effects
  • Sarcocystis / enzymology
  • Sarcocystosis / drug therapy
  • Temperature
  • Toxoplasma / drug effects
  • Toxoplasma / enzymology

Grant Funding

  • R01 AI089441 / NIAID NIH HHS
  • R01 AI111341 / NIAID NIH HHS
  • R01 GM086858 / NIGMS NIH HHS
  • R01 AI097177 / NIAID NIH HHS
  • R01 HD080670 / NICHD NIH HHS

References

This article includes 34 references
  1. Bishop AC, Shah K, Liu Y, Witucki L, Kung C, Shokat KM. Design of allele-specific inhibitors to probe protein kinase signaling.. Curr Biol 1998 Feb 26;8(5):257-66.
    pubmed: 9501066doi: 10.1016/s0960-9822(98)70198-8google scholar: lookup
  2. Castellanos-Gonzalez A, White AC Jr, Ojo KK, Vidadala RS, Zhang Z, Reid MC, Fox AM, Keyloun KR, Rivas K, Irani A, Dann SM, Fan E, Maly DJ, Van Voorhis WC. A novel calcium-dependent protein kinase inhibitor as a lead compound for treating cryptosporidiosis.. J Infect Dis 2013 Oct 15;208(8):1342-8.
    pmc: PMC3778970pubmed: 23878324doi: 10.1093/infdis/jit327google scholar: lookup
  3. Crowther GJ, Napuli AJ, Thomas AP, Chung DJ, Kovzun KV, Leibly DJ, Castaneda LJ, Bhandari J, Damman CJ, Hui R, Hol WG, Buckner FS, Verlinde CL, Zhang Z, Fan E, van Voorhis WC. Buffer optimization of thermal melt assays of Plasmodium proteins for detection of small-molecule ligands.. J Biomol Screen 2009 Jul;14(6):700-7.
    pmc: PMC2819745pubmed: 19470714doi: 10.1177/1087057109335749google scholar: lookup
  4. Dirikolu L, Karpiesiuk W, Lehner AF, Hughes C, Woods WE, Harkins JD, Boyles J, Atkinson A, Granstrom DE, Tobin T. New therapeutic approaches for equine protozoal myeloencephalitis: pharmacokinetics of diclazuril sodium salts in horses.. Vet Ther 2006 Spring;7(1):52-63, 72.
    pubmed: 16598684
  5. Doggett JS, Ojo KK, Fan E, Maly DJ, Van Voorhis WC. Bumped kinase inhibitor 1294 treats established Toxoplasma gondii infection.. Antimicrob Agents Chemother 2014 Jun;58(6):3547-9.
    pmc: PMC4068437pubmed: 24687502doi: 10.1128/aac.01823-13google scholar: lookup
  6. Dubey JP, Mattson DE, Speer CA, Baker RJ, Mulrooney DM, Tornquist SJ, Hamir AN, Gerros TC. Characterization of a Sarcocystis neurona isolate (SN6) from a naturally infected horse from Oregon.. J Eukaryot Microbiol 1999 Sep-Oct;46(5):500-6.
    pubmed: 10519218doi: 10.1111/j.1550-7408.1999.tb06067.xgoogle scholar: lookup
  7. Dubey JP, Hamir AN. Immunohistochemical confirmation of Sarcocystis neurona infections in raccoons, mink, cat, skunk, and pony.. J Parasitol 2000 Oct;86(5):1150-2.
    pubmed: 11128499doi: 10.1645/0022-3395(2000)086[1150:icosni]2.0.co;2google scholar: lookup
  8. Dubey JP, Fritz D, Lindsay DS, Shen SK, Kwok OC, Thompson KC. Diclazuril preventive therapy of gamma interferon knockout mice fed Sarcocystis neurona sporocysts.. Vet Parasitol 2001 Jan 20;94(4):257-64.
    pubmed: 11137273doi: 10.1016/s0304-4017(00)00376-9google scholar: lookup
  9. Dubey JP, Lindsay DS, Saville WJ, Reed SM, Granstrom DE, Speer CA. A review of Sarcocystis neurona and equine protozoal myeloencephalitis (EPM).. Vet Parasitol 2001 Feb 26;95(2-4):89-131.
    pubmed: 11223193doi: 10.1016/s0304-4017(00)00384-8google scholar: lookup
  10. Dubey JP, Calero-Bernal R, Rosenthal BM, Speer CA, Fayer R. Sarcocystosis of Animals and Humans. Second.
  11. Dubey JP, Howe DK, Furr M, Saville WJ, Marsh AE, Reed SM, Grigg ME. An update on Sarcocystis neurona infections in animals and equine protozoal myeloencephalitis (EPM).. Vet Parasitol 2015 Apr 15;209(1-2):1-42.
    pmc: PMC4461864pubmed: 25737052doi: 10.1016/j.vetpar.2015.01.026google scholar: lookup
  12. Ellison S, Lindsay DS. Decoquinate Combined with Levamisole Reduce the Clinical Signs and Serum SAG 1, 5, 6 Antibodies in Horses with Suspected Equine Protozoal Myeloencephalitis. Int. J. Applied Res Vet Med 2012;10:1–7.
  13. Furr M, Kennedy T, MacKay R, Reed S, Andrews F, Bernard B, Bain F, Byars D. Efficacy of ponazuril 15% oral paste as a treatment for equine protozoal myeloencephalitis.. Vet Ther 2001 Summer;2(3):215-22.
    pubmed: 19746664
  14. Gaji RY, Zhang D, Breathnach CC, Vaishnava S, Striepen B, Howe DK. Molecular genetic transfection of the coccidian parasite Sarcocystis neurona.. Mol Biochem Parasitol 2006 Nov;150(1):1-9.
    pubmed: 16844242doi: 10.1016/j.molbiopara.2006.06.003google scholar: lookup
  15. Hines SA, Ramsay JD, Kappmeyer LS, Lau AO, Ojo KK, Van Voorhis WC, Knowles DP, Mealey RH. Theileria equi isolates vary in susceptibility to imidocarb dipropionate but demonstrate uniform in vitro susceptibility to a bumped kinase inhibitor.. Parasit Vectors 2015 Jan 20;8:33.
    pmc: PMC4311422pubmed: 25600252doi: 10.1186/s13071-014-0611-6google scholar: lookup
  16. Huang W, Ojo KK, Zhang Z, Rivas K, Vidadala RS, Scheele S, DeRocher AE, Choi R, Hulverson MA, Barrett LK, Bruzual I, Siddaramaiah LK, Kerchner KM, Kurnick MD, Freiberg GM, Kempf D, Hol WG, Merritt EA, Neckermann G, de Hostos EL, Isoherranen N, Maly DJ, Parsons M, Doggett JS, Van Voorhis WC, Fan E. SAR Studies of 5-Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors of Toxoplasma gondii CDPK1.. ACS Med Chem Lett 2015 Dec 10;6(12):1184-1189.
    pmc: PMC4677665pubmed: 26693272doi: 10.1021/acsmedchemlett.5b00319google scholar: lookup
  17. Johnson SM, Murphy RC, Geiger JA, DeRocher AE, Zhang Z, Ojo KK, Larson ET, Perera BG, Dale EJ, He P, Reid MC, Fox AM, Mueller NR, Merritt EA, Fan E, Parsons M, Van Voorhis WC, Maly DJ. Development of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitors with potent anti-toxoplasma activity.. J Med Chem 2012 Mar 8;55(5):2416-26.
    pmc: PMC3306180pubmed: 22320388doi: 10.1021/jm201713hgoogle scholar: lookup
  18. Lourido S, Shuman J, Zhang C, Shokat KM, Hui R, Sibley LD. Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma.. Nature 2010 May 20;465(7296):359-62.
    doi: 10.1038/nature09022pmc: PMC2874977pubmed: 20485436google scholar: lookup
  19. Lourido S, Tang K, Sibley LD. Distinct signalling pathways control Toxoplasma egress and host-cell invasion.. EMBO J 2012 Dec 12;31(24):4524-34.
    pmc: PMC3545288pubmed: 23149386doi: 10.1038/emboj.2012.299google scholar: lookup
  20. MacKay RJ. Equine Protozoal Myeloencephalitis: Treatment, Prognosis, and Prevention. Clin Tech Equine Pract 2006;5:9–16.
  21. Mackay RJ, Tanhauser ST, Gillis KD, Mayhew IG, Kennedy TJ. Effect of intermittent oral administration of ponazuril on experimental Sarcocystis neurona infection of horses.. Am J Vet Res 2008 Mar;69(3):396-402.
    pubmed: 18312139doi: 10.2460/ajvr.69.3.396google scholar: lookup
  22. Marr CM, Reef VB, Reimer JM, Sweeney RW, Reid SW. An echocardiographic study of atrial fibrillation in horses: before and after conversion to sinus rhythm.. J Vet Intern Med 1995 Sep-Oct;9(5):336-40.
    pubmed: 8531180doi: 10.1111/j.1939-1676.1995.tb01094.xgoogle scholar: lookup
  23. Martinez Molina D, Jafari R, Ignatushchenko M, Seki T, Larsson EA, Dan C, Sreekumar L, Cao Y, Nordlund P. Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay.. Science 2013 Jul 5;341(6141):84-7.
    pubmed: 23828940doi: 10.1126/science.1233606google scholar: lookup
  24. McClure SR, Palma KG. Treatment of equine protozoal myeloencephalitis with nitazoxanide. J. Equine Vet Science 1999;19:639–641.
  25. Murphy RC, Ojo KK, Larson ET, Castellanos-Gonzalez A, Perera BG, Keyloun KR, Kim JE, Bhandari JG, Muller NR, Verlinde CL, White AC Jr, Merritt EA, Van Voorhis WC, Maly DJ. Discovery of Potent and Selective Inhibitors of Calcium-Dependent Protein Kinase 1 (CDPK1) from C. parvum and T. gondii.. ACS Med Chem Lett 2010 Oct 14;1(7):331-335.
    pmc: PMC2992447pubmed: 21116453doi: 10.1021/ml100096tgoogle scholar: lookup
  26. Ojo KK, Larson ET, Keyloun KR, Castaneda LJ, Derocher AE, Inampudi KK, Kim JE, Arakaki TL, Murphy RC, Zhang L, Napuli AJ, Maly DJ, Verlinde CL, Buckner FS, Parsons M, Hol WG, Merritt EA, Van Voorhis WC. Toxoplasma gondii calcium-dependent protein kinase 1 is a target for selective kinase inhibitors.. Nat Struct Mol Biol 2010 May;17(5):602-7.
    pmc: PMC2896873pubmed: 20436472doi: 10.1038/nsmb.1818google scholar: lookup
  27. Ojo KK, Arakaki TL, Napuli AJ, Inampudi KK, Keyloun KR, Zhang L, Hol WG, Verlinde CL, Merritt EA, Van Voorhis WC. Structure determination of glycogen synthase kinase-3 from Leishmania major and comparative inhibitor structure-activity relationships with Trypanosoma brucei GSK-3.. Mol Biochem Parasitol 2011 Apr;176(2):98-108.
    pmc: PMC3045540pubmed: 21195115doi: 10.1016/j.molbiopara.2010.12.009google scholar: lookup
  28. Ojo KK, Eastman RT, Vidadala R, Zhang Z, Rivas KL, Choi R, Lutz JD, Reid MC, Fox AM, Hulverson MA, Kennedy M, Isoherranen N, Kim LM, Comess KM, Kempf DJ, Verlinde CL, Su XZ, Kappe SH, Maly DJ, Fan E, Van Voorhis WC. A specific inhibitor of PfCDPK4 blocks malaria transmission: chemical-genetic validation.. J Infect Dis 2014 Jan 15;209(2):275-84.
    pmc: PMC3873787pubmed: 24123773doi: 10.1093/infdis/jit522google scholar: lookup
  29. Ojo KK, Reid MC, Kallur Siddaramaiah L, Müller J, Winzer P, Zhang Z, Keyloun KR, Vidadala RS, Merritt EA, Hol WG, Maly DJ, Fan E, Van Voorhis WC, Hemphill A. Neospora caninum calcium-dependent protein kinase 1 is an effective drug target for neosporosis therapy.. PLoS One 2014;9(3):e92929.
    pmc: PMC3969379pubmed: 24681759doi: 10.1371/journal.pone.0092929google scholar: lookup
  30. Pollard CE, Abi Gerges N, Bridgland-Taylor MH, Easter A, Hammond TG, Valentin JP. An introduction to QT interval prolongation and non-clinical approaches to assessing and reducing risk.. Br J Pharmacol 2010 Jan;159(1):12-21.
    pmc: PMC2823347pubmed: 20141516doi: 10.1111/j.1476-5381.2009.00207.xgoogle scholar: lookup
  31. Studier FW. Protein production by auto-induction in high density shaking cultures.. Protein Expr Purif 2005 May;41(1):207-34.
    pubmed: 15915565doi: 10.1016/j.pep.2005.01.016google scholar: lookup
  32. Vidadala RS, Rivas KL, Ojo KK, Hulverson MA, Zambriski JA, Bruzual I, Schultz TL, Huang W, Zhang Z, Scheele S, DeRocher AE, Choi R, Barrett LK, Siddaramaiah LK, Hol WG, Fan E, Merritt EA, Parsons M, Freiberg G, Marsh K, Kempf DJ, Carruthers VB, Isoherranen N, Doggett JS, Van Voorhis WC, Maly DJ. Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis.. J Med Chem 2016 Jul 14;59(13):6531-46.
    pmc: PMC5100899pubmed: 27309760doi: 10.1021/acs.jmedchem.6b00760google scholar: lookup
  33. Wernimont AK, Artz JD, Finerty P Jr, Lin YH, Amani M, Allali-Hassani A, Senisterra G, Vedadi M, Tempel W, Mackenzie F, Chau I, Lourido S, Sibley LD, Hui R. Structures of apicomplexan calcium-dependent protein kinases reveal mechanism of activation by calcium.. Nat Struct Mol Biol 2010 May;17(5):596-601.
    pmc: PMC3675764pubmed: 20436473doi: 10.1038/nsmb.1795google scholar: lookup
  34. Yeargan M, de Assis Rocha I, Morrow J, Graves A, Reed SM, Howe DK. A new trivalent SnSAG surface antigen chimera for efficient detection of antibodies against Sarcocystis neurona and diagnosis of equine protozoal myeloencephalitis.. J Vet Diagn Invest 2015 May;27(3):377-81.
    pubmed: 25943129doi: 10.1177/1040638715584995google scholar: lookup

Citations

This article has been cited 16 times.
  1. Hunt AG, Howe DK, Brown A, Yeargan M. Transcriptional dynamics in the protozoan parasite Sarcocystis neurona and mammalian host cells after treatment with a specific inhibitor of apicomplexan mRNA polyadenylation. PLoS One 2021;16(10):e0259109.
    doi: 10.1371/journal.pone.0259109pubmed: 34710156google scholar: lookup
  2. Anghel N, Imhof D, Winzer P, Balmer V, Ramseier J, Haenggeli K, Choi R, Hulverson MA, Whitman GR, Arnold SLM, Ojo KK, Van Voorhis WC, Doggett JS, Ortega-Mora LM, Hemphill A. Endochin-like quinolones (ELQs) and bumped kinase inhibitors (BKIs): Synergistic and additive effects of combined treatments against Neospora caninum infection in vitro and in vivo. Int J Parasitol Drugs Drug Resist 2021 Dec;17:92-106.
    doi: 10.1016/j.ijpddr.2021.08.007pubmed: 34482255google scholar: lookup
  3. Van Voorhis WC, Hulverson MA, Choi R, Huang W, Arnold SLM, Schaefer DA, Betzer DP, Vidadala RSR, Lee S, Whitman GR, Barrett LK, Maly DJ, Riggs MW, Fan E, Kennedy TJ, Tzipori S, Doggett JS, Winzer P, Anghel N, Imhof D, Müller J, Hemphill A, Ferre I, Sanchez-Sanchez R, Ortega-Mora LM, Ojo KK. One health therapeutics: Target-Based drug development for cryptosporidiosis and other apicomplexa diseases. Vet Parasitol 2021 Jan;289:109336.
    doi: 10.1016/j.vetpar.2020.109336pubmed: 33418437google scholar: lookup
  4. Shrestha A, Ruttkowski B, Greber P, Whitman GR, Hulverson MA, Choi R, Michaels SA, Ojo KK, Van Voorhis WC, Joachim A. Reduced treatment frequencies with bumped kinase inhibitor 1369 are effective against porcine cystoisosporosis. Int J Parasitol Drugs Drug Resist 2020 Dec;14:37-45.
    doi: 10.1016/j.ijpddr.2020.08.005pubmed: 32861205google scholar: lookup
  5. Winzer P, Anghel N, Imhof D, Balmer V, Ortega-Mora LM, Ojo KK, Van Voorhis WC, Müller J, Hemphill A. Neospora caninum: Structure and Fate of Multinucleated Complexes Induced by the Bumped Kinase Inhibitor BKI-1294. Pathogens 2020 May 16;9(5).
    doi: 10.3390/pathogens9050382pubmed: 32429314google scholar: lookup
  6. Shrestha A, Ojo KK, Koston F, Ruttkowski B, Vidadala RSR, Dorr CS, Navaluna ED, Whitman GR, Barrett KF, Barrett LK, Hulverson MA, Choi R, Michaels SA, Maly DJ, Hemphill A, Van Voorhis WC, Joachim A. Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro. Int J Parasitol Drugs Drug Resist 2019 Aug;10:9-19.
    doi: 10.1016/j.ijpddr.2019.03.004pubmed: 30959327google scholar: lookup
  7. Scheele S, Geiger JA, DeRocher AE, Choi R, Smith TR, Hulverson MA, Vidadala RSR, Barrett LK, Maly DJ, Merritt EA, Ojo KK, Van Voorhis WC, Parsons M. Toxoplasma Calcium-Dependent Protein Kinase 1 Inhibitors: Probing Activity and Resistance Using Cellular Thermal Shift Assays. Antimicrob Agents Chemother 2018 Jun;62(6).
    doi: 10.1128/AAC.00051-18pubmed: 29555627google scholar: lookup
  8. Bowden GD, Land KM, O'Connor RM, Fritz HM. High-throughput screen of drug repurposing library identifies inhibitors of Sarcocystis neurona growth. Int J Parasitol Drugs Drug Resist 2018 Apr;8(1):137-144.
    doi: 10.1016/j.ijpddr.2018.02.002pubmed: 29547840google scholar: lookup
  9. Verschueren K, Cobbaut M, Demaerel J, Saadah L, Voet ARD, Van Lint J, De Borggraeve WM. Discovery of a potent protein kinase D inhibitor: insights in the binding mode of pyrazolo[3,4-d]pyrimidine analogues. Medchemcomm 2017 Mar 1;8(3):640-646.
    doi: 10.1039/c6md00675bpubmed: 28890776google scholar: lookup
  10. Murungi EK, Kariithi HM. Genome-Wide Identification and Evolutionary Analysis of Sarcocystis neurona Protein Kinases. Pathogens 2017 Mar 21;6(1).
    doi: 10.3390/pathogens6010012pubmed: 28335576google scholar: lookup
  11. Van Voorhis WC, Doggett JS, Parsons M, Hulverson MA, Choi R, Arnold SLM, Riggs MW, Hemphill A, Howe DK, Mealey RH, Lau AOT, Merritt EA, Maly DJ, Fan E, Ojo KK. Extended-spectrum antiprotozoal bumped kinase inhibitors: A review. Exp Parasitol 2017 Sep;180:71-83.
    doi: 10.1016/j.exppara.2017.01.001pubmed: 28065755google scholar: lookup
  12. Müller J, Regidor-Cerrillo J, Arranz-Solís D, Braga-Lagache S, Uldry AC, Heller M, Calero-Bernal R, Hemphill A, Ortega-Mora LM. Proteome changes during in vitro culture adaptation of Toxoplasma gondii archetypal II and III field isolates. Front Cell Infect Microbiol 2025;15:1633384.
    doi: 10.3389/fcimb.2025.1633384pubmed: 41036225google scholar: lookup
  13. Kurhaluk N, Tkaczenko H. Recent Issues in the Development and Application of Targeted Therapies with Respect to Individual Animal Variability. Animals (Basel) 2025 Feb 6;15(3).
    doi: 10.3390/ani15030444pubmed: 39943214google scholar: lookup
  14. Dangoudoubiyam S, Norris JK, Namasivayam S, de Paula Baptista R, Cannes do Nascimento N, Camp J, Schardl CL, Kissinger JC, Howe DK. Temporal gene expression during asexual development of the apicomplexan Sarcocystis neurona. mSphere 2024 Jun 25;9(6):e0011124.
    doi: 10.1128/msphere.00111-24pubmed: 38809064google scholar: lookup
  15. Schlange C, Müller J, Imhof D, Hänggeli KPA, Boubaker G, Ortega-Mora LM, Wong HN, Haynes RK, Van Voorhis WC, Hemphill A. Single and combination treatment of Toxoplasma gondii infections with a bumped kinase inhibitor and artemisone in vitro and with artemiside in experimentally infected mice. Exp Parasitol 2023 Dec;255:108655.
    doi: 10.1016/j.exppara.2023.108655pubmed: 37981259google scholar: lookup
  16. Imhof D, Anghel N, Winzer P, Balmer V, Ramseier J, Hänggeli K, Choi R, Hulverson MA, Whitman GR, Arnold SLM, Ojo KK, Van Voorhis WC, Doggett JS, Ortega-Mora LM, Hemphill A. In vitro activity, safety and in vivo efficacy of the novel bumped kinase inhibitor BKI-1748 in non-pregnant and pregnant mice experimentally infected with Neospora caninum tachyzoites and Toxoplasma gondii oocysts. Int J Parasitol Drugs Drug Resist 2021 Aug;16:90-101.
    doi: 10.1016/j.ijpddr.2021.05.001pubmed: 34030110google scholar: lookup
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