1. Effects of dihydroorotate dehydrogenase (DHODH) inhibitors on the growth of Theileria equi and Babesia caballi in vitro.
- Author
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Kamyingkird K, Cao S, Tuvshintulga B, Salama A, Mousa AA, Efstratiou A, Nishikawa Y, Yokoyama N, Igarashi I, and Xuan X
- Subjects
- Amino Acid Sequence, Animals, Antiprotozoal Agents pharmacology, Atovaquone pharmacology, Babesia classification, Babesia growth & development, Babesiosis drug therapy, Babesiosis parasitology, Biphenyl Compounds pharmacology, Computational Biology, Dihydroorotate Dehydrogenase, Diminazene analogs & derivatives, Diminazene pharmacology, Enzyme Inhibitors therapeutic use, Horse Diseases drug therapy, Horse Diseases parasitology, Horses, Inhibitory Concentration 50, Isoxazoles pharmacology, Leflunomide, Mice, Molecular Weight, Oxidoreductases Acting on CH-CH Group Donors chemistry, Phylogeny, Plasmodium berghei drug effects, Plasmodium berghei growth & development, Pyrimidines pharmacology, Pyrimidines therapeutic use, Theileria classification, Theileria growth & development, Theileriasis drug therapy, Theileriasis parasitology, Babesia drug effects, Enzyme Inhibitors pharmacology, Oxidoreductases Acting on CH-CH Group Donors antagonists & inhibitors, Theileria drug effects
- Abstract
Theileria equi and Babesia caballi are the causative agents of equine piroplasmosis (EP), which affects equine production in various parts of the world. However, a safe and effective drug is not currently available for treatment of EP. Dihydroorotate dehydrogenase (DHODH) is the fourth enzyme in the de novo pyrimidine synthesis pathway and has been known as a novel drug target for several apicomplexan protozoan parasites. In this study, we evaluated four DHODH inhibitors; atovaquone (ATV), leflunomide (LFN), brequinar (Breq), and 7-hydroxy-5-[1,2,4] triazolo [1,5,a] pyrimidine (TAZ) on the growth of T. equi and B. caballi in vitro and compared them to diminacene aceturate (Di) as the control drug. The growth of T. equi and B. caballi was significantly hindered by all inhibitors except TAZ. The half maximal inhibitory concentration (IC
50 ) of ATV, LFN, Breq and Di against T. equi was approximately 0.028, 109, 11 and 40 μM, respectively, whereas the IC50 of ATV, LFN, Breq and Di against B. caballi was approximately 0.128, 193, 5.2 and 16.2 μM, respectively. Using bioinformatics and Western blot analysis, we showed that TeDHODH was similar to other Babesia parasite DHODHs, and confirmed that targeting DHODHs could be useful for the development of novel chemotherapeutics for treatment of EP., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2017
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