Summary Knowledge on the cell types and cell-specific gene expression of multicellular pathogens facilitates drug discovery and allows gaining a deeper understanding of pathogen biology. By utilizing single-cell RNA sequencing (scRNA-seq), we analyzed 19,581 cells of a globally prevalent parasitic flatworm, the liver fluke Fasciola hepatica, which affects health of both humans and animals. We identified 15 distinct clusters, including stem cells, gonadal, muscle and intestinal cells. Differentiation lineages within this parasite were identified and characterized by integrating RNA velocity and spatial transcriptomics data. Furthermore, an ELF5- and TRPMPZQ-expressing cell cluster was discovered, characterized by high expression of protein kinases, including the p21-activated kinase PAK4. Treatment with a PAK4 inhibitor efficiently killed the parasites. These data provide insight into the cellular composition of a complex multicellular pathogen and demonstrate how gene expression at single-cell resolution can serve as a resource for the identification of new drug targets.
Oliver Puckelwaldt, Svenja Gramberg, Sagar Ajmera et al.· iScience· 0 citations
A substantial body of research implicates PRMTs in the pathogenesis of human diseases, primarily as oncoproteins or tumor suppressors in cancer. Starting from structure-based in silico screening of small-molecule databases, we predicted, synthesized, and assayed compounds aimed at specifically inhibiting selected PRMT family members. Unexpectedly, among several PRMT-inhibitory molecules we identified TR-07, a compound that selectively enhances the catalytic activity of PRMT1 in vitro. SAR analyses led to the design and synthesis of derivatives with increased potency in activating PRMT1 compared to TR-07 but at the cost of selectivity. TR-07 and its derivatives bind to the αY helix near the catalytic core of PRMT1. Treatment of pancreatic tumor cells with these PRMT1 activators enhanced global ADMA levels and augmented PRMT1’s apoptotic function in cell culture and mouse models. Our results establish TR-07 as the first selective, cell-active PRMT1 activator and underscore the therapeutic promise of this novel class of modulators.
Sepideh Salehipour-Bavarsad, Christian Iking, Jonas Kammertöns et al.· Journal of Medicinal Chemist...· 0 citations
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