Targeting
            <i>Toxoplasma gondii</i>
            <scp>CPSF</scp>
            3 as a new approach to control toxoplasmosis

Palencia, Andrés; Bougdour, Alexandre; Brenier-Pinchart, Marie-Pierre; Touquet, Bastien; Bertini, Rose‐Laurence; Sensi, Cristina; Vollaire, Julien; Josserand, Véronique; Easom, Eric E.; Freund, Yvonne R.; Pelloux, Hervé; Rosenthal, Philip J.; Cusack, Stephen; Hakimi, Mohamed‐Ali

doi:10.15252/emmm.201607370

Cited by 64 publications

(83 citation statements)

References 34 publications

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“…This class of imidazopyrazines inhibits phosphatidylinositol 4 kinase (PI4K) in Plasmodium falciparum (12), an activity that may explain its potent ability to control C. parvum growth in vitro and in vivo. Prior studies have identified benzoxaboroles that act on mRNA polyadenylation in P. falciparum (13), and genetic evidence supports a similar target in Toxoplasma gondii (14). Related benzoxaboroles are potent inhibitors of C. parvum growth in an in vitro model and calf model of cryptosporidiosis (15).…”

mentioning

confidence: 95%

Defining Stage-Specific Activity of Potent New Inhibitors of Cryptosporidium parvum Growth In Vitro

Funkhouser-Jones

Ravindran

Sibley

2020

mBio

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Cryptosporidium parvum and Cryptosporidium hominis have emerged as major enteric pathogens of infants in the developing world, in addition to their known importance in immunocompromised adults. Although there has been recent progress in identifying new small molecules that inhibit Cryptosporidium sp. growth in vitro or in animal models, we lack information about their mechanism of action, potency across the life cycle, and cidal versus static activities. Here, we explored four potent classes of compounds that include inhibitors that likely target phosphatidylinositol 4 kinase (PI4K), phenylalanine-tRNA synthetase (PheRS), and several potent inhibitors with unknown mechanisms of action. We utilized monoclonal antibodies and gene expression probes for staging life cycle development to define the timing of when inhibitors were active during the life cycle of Cryptosporidium parvum grown in vitro. These different classes of inhibitors targeted different stages of the life cycle, including compounds that blocked replication (PheRS inhibitors), prevented the segmentation of daughter cells and thus blocked egress (PI4K inhibitors), or affected sexual-stage development (a piperazine compound of unknown mechanism). Long-term cultivation of C. parvum in epithelial cell monolayers derived from intestinal stem cells was used to distinguish between cidal and static activities based on the ability of parasites to recover from treatment. Collectively, these approaches should aid in identifying mechanisms of action and for designing in vivo efficacy studies based on time-dependent concentrations needed to achieve cidal activity. IMPORTANCE Currently, nitazoxanide is the only FDA-approved treatment for cryptosporidiosis; unfortunately, it is ineffective in immunocompromised patients, has varied efficacy in immunocompetent individuals, and is not approved in infants under 1 year of age. Identifying new inhibitors for the treatment of cryptosporidiosis requires standardized and quantifiable in vitro assays for assessing potency, selectivity, timing of activity, and reversibility. Here, we provide new protocols for defining which stages of the life cycle are susceptible to four highly active compound classes that likely inhibit different targets in the parasite. We also utilize a newly developed long-term culture system to define assays for monitoring reversibility as a means of defining cidal activity as a function of concentration and time of treatment. These assays should provide valuable in vitro parameters to establish conditions for efficacious in vivo treatment.

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confidence: 95%

Defining Stage-Specific Activity of Potent New Inhibitors of Cryptosporidium parvum Growth In Vitro

Funkhouser-Jones

Ravindran

Sibley

2020

mBio

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“…CPSF3, an essential component for converting heteronuclear RNA to mRNA, is associated with cellular stress response 1 protein-mediated cell death [87] and also can be designed as an novel target for control toxoplasmosis[88]. The RNA binding protein FXR1 is a critical regulator of post-transcriptional gene expression in differentiation, development and immunity [89,90].…”

Section: Discussionmentioning

confidence: 99%

Deep sequencing of the mouse lung transcriptome reveals distinct long non-coding RNAs expression associated with the high virulence of H5N1 avian influenza virus in mice

Hu¹,

Hu²,

Wang³

et al. 2018

Virulence

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Long non-coding RNAs (lncRNAs) play multiple key regulatory roles in various biological processes. However, their function in influenza A virus (IAV) pathogenicity remains largely unexplored. Here, using next generation sequencing, we systemically compared the whole-transcriptome response of the mouse lung infected with either the highly pathogenic (A/Chicken/Jiangsu/k0402/2010, CK10) or the nonpathogenic (A/Goose/Jiangsu/k0403/2010, GS10) H5N1 virus. A total of 126 significantly differentially expressed (SDE) lncRNAs from three replicates were identified to be associated with the high virulence of CK10, whereas 94 SDE lncRNAs were related with GS10. Functional category analysis suggested that the SDE lncRNAs-coexpressed mRNAs regulated by CK10 were highly related with aberrant and uncontrolled inflammatory responses. Further canonical pathway analysis also confirmed that these targets were highly enriched for inflammatory-related pathways. Moreover, 9 lncRNAs and 17 lncRNAs-coexpressed mRNAs associated with a large number of targeted genes were successfully verified by qRT-PCR. One targeted lncRNA (NONMMUT011061) that was markedly activated and correlated with a great number of mRNAs was selected for further in-depth analysis, including predication of transcription factors, potential interacting proteins, genomic location, coding ability and construction of the secondary structure. More importantly, NONMMUT011061 was also distinctively stimulated during the highly pathogenic H5N8 virus infection in mice, suggesting a potential universal role of NONMMUT011061 in the pathogenesis of different H5 IAV. Altogether, these results provide a subset of lncRNAs that might play important roles in the pathogenesis of influenza virus and add the lncRNAs to the vast repertoire of host factors utilized by IAV for infection and persistence.

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“…However, among the changes in resistant lines was an amplification in the gene copy number of the RNA cleavage and polyadenylation specificity factor subunit 3 (CPSF3) [93]. Subsequently, CPSF3 was identified as a target for benzoxaboroles in apicomplexan parasites Plasmodium [93] and Toxoplasma [94]. Based on this observation, and the fact that metabolomics experiments had revealed a profound change in the methionine metabolism [95] that might have been related to RNA processing defects, particularly given the multi-methylation of the spliced leader sequence used in trans-splicing in trypanosomes, the effect of over-expression of CPSF3 on sensitivity to the related benzoxaborole, AN7973, was tested [96].…”

Section: Acoziborole: Mode Of Action and Resistance Riskmentioning

confidence: 99%

New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story

et al. 2020

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The twentieth century ended with human African trypanosomiasis (HAT) epidemics raging across many parts of Africa. Resistance to existing drugs was emerging, and many programs aiming to contain the disease had ground to a halt, given previous success against HAT and the competing priorities associated with other medical crises ravaging the continent. A series of dedicated interventions and the introduction of innovative routes to develop drugs, involving Product Development Partnerships, has led to a dramatic turnaround in the fight against HAT caused by Trypanosoma brucei gambiense. The World Health Organization have been able to optimize the use of existing tools to monitor and intervene in the disease. A promising new oral medication for stage 1 HAT, pafuramidine maleate, ultimately failed due to unforeseen toxicity issues. However, the clinical trials for this compound demonstrated the possibility of conducting such trials in the resource-poor settings of rural Africa. The Drugs for Neglected Disease initiative (DNDi), founded in 2003, has developed the first all oral therapy for both stage 1 and stage 2 HAT in fexinidazole. DNDi has also brought forward another oral therapy, acoziborole, potentially capable of curing both stage 1 and stage 2 disease in a single dosing. In this review article, we describe the remarkable successes in combating HAT through the twenty first century, bringing the prospect of the elimination of this disease into sight.

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Targeting Toxoplasma gondii CPSF 3 as a new approach to control toxoplasmosis

Cited by 64 publications

References 34 publications

Defining Stage-Specific Activity of Potent New Inhibitors of Cryptosporidium parvum Growth In Vitro

Defining Stage-Specific Activity of Potent New Inhibitors of Cryptosporidium parvum Growth In Vitro

Deep sequencing of the mouse lung transcriptome reveals distinct long non-coding RNAs expression associated with the high virulence of H5N1 avian influenza virus in mice

New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story

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