title: Effects of dihydroorotate dehydrogenase (DHODH) inhibitors on the growth of Theileria equi and Babesia caballi in vitro.
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 (IC50) of ATV, LFN, Breq and Di against T. equi was approximately 0.028, 109, 11 and 40 μM, respectively, whereas the IC50of 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.
authors.affiliation: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, 080-8555, Japan; Department of Parasitology, Faculty of Veterinary Medicine, Kasetsart University, Bangkok, 10900, Thailand.
authors.forename: Ketsarin
authors.initials: K
authors.lastname: Kamyingkird
authors.affiliation: Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Nangang District, Harbin, 150001, China.
authors.forename: Shinuo
authors.initials: S
authors.lastname: Cao
authors.affiliation: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, 080-8555, Japan.
authors.forename: Bumduuren
authors.initials: B
authors.lastname: Tuvshintulga
authors.affiliation: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, 080-8555, Japan; Department of Animal Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat City, Sadat City, 32897, Menoufia, Egypt.
authors.forename: Akram
authors.initials: A
authors.lastname: Salama
authors.affiliation: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, 080-8555, Japan; Department of Biochemistry and Chemistry of Nutrition, Faculty of Veterinary Medicine, University of Sadat City, Sadat City, 32897, Menoufia, Egypt.
authors.forename: Ahmed Abdelmoniem
authors.initials: AA
authors.lastname: Mousa
authors.affiliation: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, 080-8555, Japan.
authors.forename: Artemis
authors.initials: A
authors.lastname: Efstratiou
authors.affiliation: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, 080-8555, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Nishikawa
authors.affiliation: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, 080-8555, Japan.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Yokoyama
authors.affiliation: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, 080-8555, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Igarashi
authors.affiliation: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, 080-8555, Japan. Electronic address: gen@obihiro.ac.jp.
authors.forename: Xuenan
authors.initials: X
authors.lastname: Xuan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology; D053626:Atovaquone / Q000494:pharmacology; D001403:Babesia / Q000145:classification / Q000187:drug effects* / Q000254:growth & development; D001404:Babesiosis / Q000188:drug therapy / Q000469:parasitology; D001713:Biphenyl Compounds / Q000494:pharmacology; D019295:Computational Biology; D000090722:Dihydroorotate Dehydrogenase; D004133:Diminazene / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006734:Horse Diseases / Q000188:drug therapy / Q000469:parasitology; D006736:Horses; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000494:pharmacology; D000077339:Leflunomide; D051379:Mice; D008970:Molecular Weight; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010802:Phylogeny; D010962:Plasmodium berghei / Q000187:drug effects / Q000254:growth & development; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D016794:Theileria / Q000145:classification / Q000187:drug effects* / Q000254:growth & development; D013801:Theileriasis / Q000188:drug therapy / Q000469:parasitology; D011798:Quinaldines
chemical_list: D000981:Antiprotozoal Agents; D053626:Atovaquone; D001713:Biphenyl Compounds; D000090722:Dihydroorotate Dehydrogenase; D004133:Diminazene; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D000077339:Leflunomide; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011743:Pyrimidines; C046943:brequinar; D011798:Quinaldines; C003915:diminazene aceturate; C030986:pyrimidine
keywords: Atovaquone; Babesia caballi; Dihydroorotate dehydrogenase; Equine piroplasmosis; Theileria equi