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Glioblastoma, an invasive high-grade brain cancer, exhibits numerous treatment challenges. Amongst the current therapies, targeting functional receptors and active signaling pathways were found to be a potential approach for treating GBM. We exploited the role of endogenous expression of GPR17, a G protein-coupled receptor (GPCR), with agonist GA-T0 in the survival and treatment of GBM. RNA sequencing was performed to understand the association of GPR17 expression with LGG and GBM. RT-PCR and immunoblotting were performed to confirm the endogenous expression of GPR17 mRNA and its encoded protein. Biological functions of GPR17 in the GBM cells was assessed by in vitro analysis. HPLC and histopathology in wild mice and an acute-toxicity analysis in a patient-derived xenograft model were performed to understand the clinical implication of GA-T0 targeting GPR17. We observed the upregulation of GPR17 in association with improved survival of LGG and GBM, confirming it as a predictive biomarker. GA-T0-stimulated GPR17 leads to the inhibition of cyclic AMP and calcium flux. GPR17 signaling activation enhances cytotoxicity against GBM cells and, in patient tissue-derived mesenchymal subtype GBM cells, induces apoptosis and prevents proliferation by stoppage of the cell cycle at the G1 phase. Modulation of the key genes involved in DNA damage, cell cycle arrest, and in several signaling pathways, including MAPK/ERK, PI3K–Akt, STAT, and NF-κB, prevents tumor regression. In vivo activation of GPR17 by GA-T0 reduces the tumor volume, uncovering the potential of GA-T0–GPR17 as a targeted therapy for GBM treatment. Conclusion: Our analysis suggests that GA-T0 targeting the GPR17 receptor presents a novel therapy for treating glioblastoma.

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No current treatment options were successful in containing the ongoing pandemic COVID-19 caused by SARS-CoV-2. It is essential to understand the molecular players of SARS-CoV-2 to find a suitable treatment method and to develop an effective antiviral drug as early as possible. Global researchers have undertaken accelerated structural studies of key proteins involved in host-virus interaction, replication, and transcription. In silico studies support structural biologist with preliminary information to efficiently drive further studies and characterization. From the genome sequence, most SARS-CoV-2 annotated ORF has a conserved sequence similar to SARS-CoV-1, except for ORF8 and ORF10. The function of ORF8 protein in SARS-CoV-2 is uncertain. Herein, we had modelled the ORF8 protein and studied its putative function using various substrates as a probe to determine its biological significance. The modelled SARS-CoV-2 (mORF8) protein shows IgG characteristic folds and thus may belong to IgG superfamily. Further, we studied the binding efficacy of various antiviral drugs against the modelled ORF8 of SARS-CoV-2 (mORF8) to repurpose the drug and to use them as a probe to study its function by studying the binding/active sites interaction. Remdesivir had the highest binding affinity to ORF8 protein of SARS-CoV-2. The high affinity of the adenosine analogue yields critical information about the non-canonical RNA dependent RNA polymerase (RdRp) function of ORF8 protein. We hypothesize that the ORF8 protein may be a non-canonical RdRp in SARS-CoV-2 with ability to bind to canonical nsp12 complex.

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