A conserved intracellular allosteric binding site (IABS) was recently identified at several G protein-coupled receptors (GPCRs). This target site allows the binding of allosteric modulators and enables a new mode of GPCR inhibition. Herein, we report the development of a NanoBRET-based assay platform based on the fluorescent ligand LT221 (5), to detect intracellular binding to CCR6 and CXCR1, two chemokine receptors that have been pursued as promising drug targets in inflammation and immuno-oncology. Our assay platform enables cell-free as well as cellular NanoBRET-based binding studies in a nonisotopic and straightforward manner. By combining this screening platform with a previously reported CXCR2 assay, we investigated CXCR1/CXCR2/CCR6 selectivity profiles for both known and novel squaramide analogues derived from navarixin, a known intracellular CXCR1/CXCR2 antagonist and phase II clinical candidate for the treatment of pulmonary diseases. By means of these studies we identified compound 10, a previously reported tert-butyl analogue of navarixin, as a low nanomolar intracellular CCR6 antagonist. Further, our assay platform clearly indicated intracellular binding of the CCR6 antagonist PF-07054894, currently evaluated in phase I clinical trials for the treatment of ulcerative colitis, thereby providing profound evidence for the existence and the pharmacological relevance of a druggable IABS at CCR6.
Botswana, like the rest of the world, has been significantly impacted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In December 2022, we detected a monophyletic cluster of genomes comprising a sublineage of the Omicron variant of concern (VOC) designated as B.1.
High-throughput chemistry (HTC) and direct-to-biology (D2B) platforms allow for plate-based compound synthesis and biological evaluation of crude mixtures in cellular assays. The rise of these workflows has rapidly accelerated drug-discovery programs in the field of targeted protein degradation (TPD) in recent years by removing a key bottleneck of compound purification. However, the number of chemical transformations amenable to this methodology remain minimal, leading to limitations in the exploration of chemical space using existing library-based approaches.
During the Russia-Ukraine war, Ukrainian President Volodymyr Zelenskyy has strategically used social media to appeal for international support. This reflects a broader trend of political figures relying on digital platforms to shape public opinion and influence global narratives during crises. This work uses three main analysis methods, content, sentiment and social network analysis.
Artificial Intelligence & Mathematical Modeling Lab (AIMM Lab), Dalla Lana School of Public Health, University of Toronto, 155 College St Room 500, Toronto, ON, M5T 3M7, Canada.
Acute flaccid paralysis (AFP) case surveillance is pivotal for the early detection of potential poliovirus, particularly in endemic countries such as Ethiopia. The community-based surveillance system implemented in Ethiopia has significantly improved AFP surveillance. However, challenges like delayed detection and disorganized communication persist.
Background And Purpose: Psoriasis is a chronic, immune-mediated inflammatory skin disease that significantly impacts patients' quality of life. The integration of telepharmacy has the potential to enhance patient care by providing flexible and personalized pharmaceutical follow-up. This study (TELEPROM Psoriasis) evaluates a telepharmacy model for evaluating electronic Patient-Reported outcomes (ePROMs) for individuals with moderate to severe plaque psoriasis in Spain with biological treatment.
