Chhaminder Kaur

All Publications

• High-Throughput Screening to Identify Inhibitors of Plasmodium falciparum Importin α. Cells Walunj, S. B., Dias, M. M., Kaur, C., Wagstaff, K. M., Dey, V., Hick, C., Patankar, S., Jans, D. A. 2022; 11 (7)

  Abstract

  The global burden of malaria and toxoplasmosis has been limited by the use of efficacious anti-parasitic agents, however, emerging resistance in Plasmodium species and Toxoplasma gondii threatens disease control worldwide, implying that new agents/therapeutic targets are urgently needed. Nuclear localization signal (NLS)-dependent transport into the nucleus, mediated by members of the importin (IMP) superfamily of nuclear transporters, has shown potential as a target for intervention to limit viral infection. Here, we show for the first time that IMPα from P. falciparum and T. gondii have promise as targets for small molecule inhibitors. We use high-throughput screening to identify agents able to inhibit P. falciparum IMPα binding to a P. falciparum NLS, identifying a number of compounds that inhibit binding in the µM-nM range, through direct binding to P. falciparum IMPα, as shown in thermostability assays. Of these, BAY 11-7085 is shown to be a specific inhibitor of P. falciparum IMPα-NLS recognition. Importantly, a number of the inhibitors limited growth by both P. falciparum and T. gondii. The results strengthen the hypothesis that apicomplexan IMPα proteins have potential as therapeutic targets to aid in identifying novel agents for two important, yet neglected, parasitic diseases.

  View details for DOI 10.3390/cells11071201

  View details for PubMedID 35406765

  View details for PubMedCentralID PMC8997399

• The role of upstream open reading frames in translation regulation in the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii. Parasitology Kaur, C., Patankar, S. 2021; 148 (11): 1277-1287

  Abstract

  During their complex life cycles, the Apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii employ several layers of regulation of their gene expression. One such layer is mediated at the level of translation through upstream open reading frames (uORFs). As uORFs are found in the upstream regions of a majority of transcripts in both the parasites, it is essential that their roles in translational regulation be appreciated to a greater extent. This review provides a comprehensive summary of studies that show uORF-mediated gene regulation in these parasites and highlights examples of clinically and physiologically relevant genes, including var2csa in P. falciparum, and ApiAT1 in T. gondii, that exhibit uORF-mediated regulation. In addition to these examples, several studies that use bioinformatics, transcriptomics, proteomics and ribosome profiling also indicate the possibility of widespread translational regulation by uORFs. Further analysis of these genome-wide datasets, taking into account uORFs associated with each gene, will reveal novel genes involved in key biological pathways such as cell-cycle progression, stress-response and pathogenicity. The cumulative evidence from studies presented in this review suggests that uORFs will play crucial roles in regulating gene expression during clinical disease caused by these important human pathogens.

  View details for DOI 10.1017/S0031182021000937

  View details for PubMedID 34099078

  View details for PubMedCentralID PMC8383288

• Messenger RNAs with large numbers of upstream open reading frames are translated via leaky scanning and reinitiation in the asexual stages of Plasmodium falciparum. Parasitology Kaur, C., Kumar, M., Patankar, S. 2020; 147 (10): 1100-1113

  Abstract

  The genome of Plasmodium falciparum has one of the most skewed base-pair compositions of any eukaryote, with an AT content of 80-90%. As start and stop codons are AT-rich, the probability of finding upstream open reading frames (uORFs) in messenger RNAs (mRNAs) is high and parasite mRNAs have an average of 11 uORFs in their leader sequences. Similar to other eukaryotes, uORFs repress the translation of the downstream open reading frame (dORF) in P. falciparum, yet the parasite translation machinery is able to bypass these uORFs and reach the dORF to initiate translation. This can happen by leaky scanning and/or reinitiation.In this report, we assessed leaky scanning and reinitiation by studying the effect of uORFs on the translation of a dORF, in this case, the luciferase reporter gene, and showed that both mechanisms are employed in the asexual blood stages of P. falciparum. Furthermore, in addition to the codon usage of the uORF, translation of the dORF is governed by the Kozak sequence and length of the uORF, and inter-cistronic distance between the uORF and dORF. Based on these features whole-genome data was analysed to uncover classes of genes that might be regulated by uORFs. This study indicates that leaky scanning and reinitiation appear to be widespread in asexual stages of P. falciparum, which may require modifications of existing factors that are involved in translation initiation in addition to novel, parasite-specific proteins.

  View details for DOI 10.1017/S0031182020000840

  View details for PubMedID 32450933

  View details for PubMedCentralID PMC10317768