Orphan GPCRs of the GPRC5 family regulate macrophage activity and vascular contractility by dimerizing with other GPCRs, but pharmacological modulation of this process has not been explored. We previously identified the dimerization interface of receptor GPRC5B and show here that both its mutation and inhibition by a decoy peptide disturbed the interaction with the prostaglandin E2 receptor EP2 in macrophages, resulting in reduced EP2 signaling, enhanced migration and phagocytosis, and protection from bacterial peritonitis in mice. Furthermore, we show that a similar interface exists in related receptor GPRC5C, and, the same as in GPRC5B, mutation or inhibition by decoy peptide improved host defense. Through a virtual docking screen, we identified a small molecule inhibitor of both GPRC5B and GPRC5C dimerization, K303MP20, and showed that it reduced EP2 signaling, enhanced macrophage activity, and improved host defense in bacterial peritonitis and influenza A infection. Interestingly, K303MP20 not only blocked dimerization between GPRC5B/C and EP2, but also with prostacyclin receptor IP and angiotensin II receptor AT1, resulting in reduced AT1-dependent contraction and enhanced IP-dependent relaxation in human and murine smooth muscle cells. In vivo, K303MP20 did not affect basal blood pressure, but protected mice from angiotensin II–induced hypertension. Taken together, inhibition of orphan GPCR dimerization by small molecules is feasible and improves infection control and arterial hypertension.
Jeonghyeon Kwon, Margherita Persechino, Jingchen Shao et al.· Journal of Clinical Investig...· 0 citations
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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