Rechts der Isar Hospital

GPR3 belongs to the protein superfamily of G protein-coupled receptors (GPCRs) and plays a central role in both benign and malignant physiological processes, such as energy expenditure in adipocytes and Alzheimer's disease pathology, respectively. Despite the therapeutic potential of both receptor agonists and inverse agonists, GPR3 so far has lacked drug-like ligands and innovative screening technologies, hindering effective drug discovery efforts targeting this receptor. To overcome the limitations of conventional ligand screening techniques based on cAMP accumulation or β-arrestin recruitment, we developed a conformational GPR3 biosensor to monitor receptor activity in living cells with high-throughput screening (HTS)-compatible sensitivity and robustness. Combined with virtual compound screening against homology models of GPR3 and classical medicinal chemistry, this biosensor enabled us to identify new ligands, one of which (compound 33) modulates GPR3-dependent Gs activity with an average potency in the nanomolar range. Our study not only presents novel GPR3 ligands for future optimization efforts and paves the way for even further expansion of the GPR3 ligand repertoire, but our sensor approach also provides a blueprint for targeting other therapeutically attractive yet challenging orphan GPCRs.

Background:Understanding the prevalence of pneumococcal serotypes in hospitalised patients with community-acquired pneumonia (CAP) is critical for vaccine development and implementation of future public health policies. Pneumococcal conjugate vaccines (PCVs) have been implemented to decrease the burden of pneumococcal disease. This study aims to identify the serotype distribution of pneumococcal CAP in Germany. Methods:This interim analysis of a multicentre, prospective, active observational study includes patients aged ≥18 years hospitalised with CAP in seven German hospitals. Patients were enrolled between August 2022 and September 2024. To determine CAP aetiology, microbiological tests were performed according to local standard of care. Urinary antigen testing for Streptococcus pneumoniae (BinaxNOW) was performed in all patients, and two serotype-specific urinary antigen detection (SSUAD) assays were used to detect serotypes in pneumococcal vaccines PCV15 and PCV20. Results:S. pneumoniae was detected in 16.5% (85/514) of participants by all diagnostic tests. SSUAD assays detected S. pneumoniae as pathogen in 13.2% (68/514) of participants. In six patients, two pneumococcal serotypes were detected. The seven most detected serotypes were: 3, 11A, 8, 23B, 9N, 18C and 22F. Among 74 serotype detections, 64 (86.9%) are included in V116 compared with 56 (75.8%) in PCV20. The difference in coverage between PCV20 and V116 was 10.8% (95% CI -3.2-24.8%). Conclusion:Among adults hospitalised with CAP in Germany, S. pneumoniae was detected in 13% of cases by SSUAD assays. While the findings suggest that V116 may offer broader serotype coverage compared with PCV20, these differences were not statistically significant.

In Deutschland sind gegenwärtig mindestens 1,8 Millionen von Demenz betroffen; bis 2060 droht ein Anstieg auf 2,1 Millionen Betroffene. Prävention bietet die derzeit beste Möglichkeit zur effektiven Linderung der Krankheitslast. Das Krankheitsrisiko und der Krankheitsverlauf sowie die Effektivität von Präventionsmaßnahmen werden von diversen Faktoren beeinflusst; in Kombination ergeben diese potenziell individuelle Risikoprofile als Grundlage für eine effektive Demenzprävention. Die Hebung dieser Potenziale erfordert kurzfristig insbesondere eine bessere Nutzung bestehender Daten inklusive einer erweiterten Datenerfassung und Nutzbarmachung für die Forschung, wodurch bevölkerungsbasierte Screening- und Interventionsmaßnahmen entwickelt und eine Strategie zur personalisierten Demenzprävention realisiert werden können.