1887

Abstract

The poultry disease coccidiosis, caused by infection with spp. apicomplexan parasites, is responsible for enormous economic losses to the global poultry industry. The rapid increase of resistance to therapeutic agents, as well as the expense of vaccination with live attenuated vaccines, requires the development of new effective treatments for coccidiosis. Because of their key regulatory function in the eukaryotic cell cycle, cyclin-dependent kinases (CDKs) are prominent drug targets. The CDC2-related kinase 2 (EtCRK2) is a validated drug target that can be activated by the CDK activator XlRINGO ( apid nducer of 2/M rogression in ocytes). Bioinformatics analyses revealed four putative cyclins (EtCYCs) that are closely related to cyclins found in the human apicomplexan parasite . EtCYC3a was cloned, expressed in and purified in a complex with EtCRK2. Using the non-radioactive time-resolved fluorescence energy transfer (TR-FRET) assay, we demonstrated the ability of EtCYC3a to activate EtCRK2 as shown previously for XlRINGO. The EtCRK2/EtCYC3a complex was used for a combined and high-throughput screening approach, which resulted in three lead structures, a naphthoquinone, an 8-hydroxyquinoline and a 2-pyrimidinyl-aminopiperidine-propane-2-ol. This constitutes a promising starting point for the subsequent lead optimization phase and the development of novel anticoccidial drugs.

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2012-09-01
2021-10-18
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