ORCID Profile
0000-0002-9739-7774
Current Organisation
INSERM
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Publisher: American Society for Microbiology
Date: 25-04-2023
Abstract: Toxoplasma infection causes serious complications in immunocompromised in iduals and in the developing fetus. During infection, certain immune cells release a protein called interferon gamma that activates cells to destroy the parasite or inhibit its growth.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-08-2022
DOI: 10.1126/SCITRANSLMED.ABN3231
Abstract: The Apicomplexa comprise a large phylum of single-celled, obligate intracellular protozoa that include
Publisher: Cold Spring Harbor Laboratory
Date: 03-11-2021
DOI: 10.1101/2021.11.03.467097
Abstract: 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 repurposing 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 Tg PRP4K of T. gondii as the primary target of altiratinib by genetic target deconvolution, highlighting key residues within the kinase catalytic site that, when mutated, confer resistance to the drug. We have further elucidated the molecular basis of the inhibitory mechanism and species selectivity of altiratinib for Tg PRP4K as well as for its P. falciparum counterpart Pf CLK3. Our data also point to structural features critical for binding of the other Pf CLK3 inhibitor, TCMDC-135051. Consistent with the role of this kinase family in splicing in a broad spectrum of eukaryotes, we have shown that altiratinib causes global disruption of splicing, primarily through intron retention in both T. gondii and P. falciparum . Thus, our data establish parasitic PRP4K/CLK3 as a promising pan-apicomplexan target whose repertoire of inhibitors can be expanded by the addition of altiratinib.
Publisher: eLife Sciences Publications, Ltd
Date: 15-07-2021
DOI: 10.7554/ELIFE.68312
Abstract: Correct 3’end processing of mRNAs is one of the regulatory cornerstones of gene expression. In a parasite that must adapt to the regulatory requirements of its multi-host life style, there is a need to adopt additional means to partition the distinct transcriptional signatures of the closely and tandemly arranged stage-specific genes. In this study, we report our findings in T. gondii of an m6A-dependent 3’end polyadenylation serving as a transcriptional barrier at these loci . We identify the core polyadenylation complex within T. gondii and establish CPSF4 as a reader for m6A-modified mRNAs, via a YTH domain within its C-terminus, a feature which is shared with plants. We bring evidence of the specificity of this interaction both biochemically, and by determining the crystal structure at high resolution of the T. gondii CPSF4-YTH in complex with an m6A-modified RNA. We show that the loss of m6A, both at the level of its deposition or its recognition is associated with an increase in aberrantly elongated chimeric mRNAs emanating from impaired transcriptional termination, a phenotype previously noticed in the plant model Arabidopsis thaliana . Nanopore direct RNA sequencing shows the occurrence of transcriptional read-through breaching into downstream repressed stage-specific genes, in the absence of either CPSF4 or the m6A RNA methylase components in both T. gondii and A. thaliana . Taken together, our results shed light on an essential regulatory mechanism coupling the pathways of m6A metabolism directly to the cleavage and polyadenylation processes, one that interestingly seem to serve, in both T. gondii and A. thaliana , as a guardian against aberrant transcriptional read-throughs.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Christopher Swale.