Molidustat Sodium

Airborne RNA viruses of the Paramyxoviridae family are major human pathogens. These include measles virus (MeV) and Nipah virus (NiV), the latter being on the World Health Organization's blueprint list due to its high case-fatality rate and critical risk of emergence. Although an effective vaccine is available for MeV, this is not the case for NiV. Moreover, there is no cure for MeV- or NiV-infected patients that prevents the acute respiratory syndrome or lethal encephalitis. To identify new host factors to target for inhibiting viral growth, a library of metabolic modulators was screened for activity against MeV using an in vitro infection model. Results showed that Molidustat, a pharmacological inhibitor of Prolyl-Hydroxylase Domain (PHD) enzymes, inhibits MeV infection in a Hypoxia-Inducible Factor (HIF)-dependent manner. We then tested the antiviral effect of Molidustat in organotypic cultures of hamster cerebellum. Molidustat induced the hypoxia-response pathway in this ex vivo model as assessed by transcriptomic analysis, and inhibited MeV infection. A similar antiviral effect was observed with Roxadustat and Daprodustat, two PHD enzyme inhibitors chemically unrelated to Molidustat. Finally, we showed that Molidustat inhibits NiV infection in organotypic cultures of hamster cerebellum and lung, thereby validating its effect in the two organs mainly targeted during infection. Taken together, our results provide evidence that pharmacological activation of the hypoxia-response pathway restricts MeV and NiV infections, highlighting HIF-inducing drugs as promising candidates to consider in the development of treatments.

Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHI) are to increase the production of EPO and haemoglobin in patients with chronic kidney disease. HIF inhibitors such as Molidustat and Vadadustat are used as doping agents in racing sports. We present new sensitive and selective materials for the biosensing of Molidustat and Vadadustat in aqueous solution and saliva. Plasmonic nickel foam was synthesised using a reproducible chemical method that deposits forests of closely packed cauliflower-shaped gold nanostructures on the nickel surface. The plasmonic material showed a high enhancement factor of Raman signals (1.09 × 10 7 ). Therefore, it was used as a sensor for the detection of HIF inhibitors by surface-enhanced Raman spectroscopy (SERS). A target-specific extractor chip for HIF-PHI was fabricated by functionalising the plasmonic nickel foam with prolyl hydroxylase domain-containing protein 2 (PHD2) molecules. The surface functionalisation was carried out by a green synthesis process that utilises deep UV LED light to convert the PHD2 molecule into a bio-thiol that attaches to the plasmonic nickel foam via Au–S bonds. Using the new SERS sensor and extractor chip, Molidustat and Vadadustat were quantified in aqueous solution down to 0.01 µg/L. The new materials were also utilised for the rapid screening of HIF-PHI in spiked saliva samples. The new materials and light-driven surface functionalisation process can be easily adopted to develop new screening methods for multiple biomolecules (e.g. drugs, proteins, disease biomarkers, environmental toxins) for many applications (e.g. therapeutic drug monitoring, doping control, clinical diagnostics environmental monitoring). Graphical Abstract