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ABSTRACT: Altiratinib blocks Toxoplasma gondii and Plasmodium falciparum development by selectively targeting a spliceosome kinase

PROVIDER: PRJNA774463 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16572002_1.fastq.gz	Fastqsanger.gz
	SRR16572003_1.fastq.gz	Fastqsanger.gz
	SRR16572004_1.fastq.gz	Fastqsanger.gz
	SRR16572005_1.fastq.gz	Fastqsanger.gz
	SRR16572006_1.fastq.gz	Fastqsanger.gz

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Altiratinib blocks Toxoplasma gondii and Plasmodium falciparum development by selectively targeting a kinase critical for splicing

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Project description:The apicomplexa comprise a large phylum of single-celled, obligate intracellular protozoa that infect humans and animals and cause severe parasitic diseases. Available therapeutics against these devastating diseases are limited by suboptimal efficacy and frequent side effects, as well as the emergence and spread of resistance. Here, we use a drug repositioning strategy and identify altiratinib, a compound originally developed to treat glioblastoma, as a promising drug candidate with broad spectrum activity against apicomplexans. Altiratinib is parasiticidal and blocks the development of intracellular zoites in the nanomolar range and with a high selectivity index. We have identified TgPRP4K of T. gondii as the primary target of altiratinib by genetic target deconvolution. TgPRP4K is phylogenetically related to the cyclin-dependent-like kinase family (CLK) and its closest ancestor in humans is the splicing factor kinase PRP4 kinase (PRP4K or PRPF4B) and in P. falciparum is PfCLK3 (PF3D7_1114700), a kinase that has been identified as a multistage cross-species antimalarial drug target. We found an altiratinib-resistant parasite line has a wild-type (WT) allele of TgPRP4K and a mutation E1325K in TgPRP8, a protein located in the catalytic core of the spliceosome that has been shown to interact with PRP4K in Schizosaccharomyces pombe to facilitate spliceosome activation. This reinforces the possibility that the PRP4K-PRP8 complex is at the basis for the anti-Toxoplasma activity of altiratinib. To gain insight about the role of both proteins in T. gondii, we characterized their interactomes.

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