Periodic Reporting for period 3 - RespiriTB (Progress new assets (one pre-new molecular entity and one first-time-in-human start) for tuberculosis that act synergistically with bedaquiline, cytochrome bc or cytochrome bd inhibitors)
Periodo di rendicontazione: 2021-05-01 al 2022-04-30
Results 1 - cytochromes. We have progressed one of the selected cytochrome inhibitors through pre-clinical studies to prepare it for Phase-I clinical trials. In addition, we have extracted and purified the cytochrome bc and cytochrome bd complexes to study their interaction with the inhibitors using biochemical and structural methods. This way we will be able to improve the potency of the inhibitors as well as study drug resistance inducing mutations in order to create novel inhibitor versions that are less susceptible to resistance inducing mutations.
Results 2 - Mycothione reductase. Since the beginning of the project, we extracted and purified the mycothione reductase protein and used it to identify novel inhibitors. These novel inhibitors are currently being evaluated so that a small set of these can be selected to enter the drug development pipeline. The mycothione reductase protein will also be used for structural studies to improve our understanding of inhibitor binding and increase their potency and selectivity.
Results 3 - host directed therapies. We have created a small set of host-directed inhibitors that reduce the growth of the bacterium within the human cell. These compounds are currently evaluated further to create a smaller selection that will enter the drug development pipeline.