Thioredoxin reductases (TrxRs) are key targets for treating infectious and inflammatory diseases. Selective inhibition of TrxRs is challenging due to a focus on irreversible mechanisms. Research on the TrxR from Schistosoma mansoni, a human parasite causing schistosomiasis, revealed a new "doorstop pocket" in the enzyme. This led to the development of novel TrxR inhibitors that outperform praziquantel, the standard schistosomiasis treatment, effective against both mature and juvenile stages of the parasite. Inhibition via small molecules at the doorstop pocket is promising, as this pocket exists in all TrxRs, including human TrxR1. Preliminary studies show that inhibitors designed for Schistosoma's TrxR can also inhibit the human version. Human TrxR1 and thioredoxin, its substrate, regulate the inflammasome, suggesting potential as new anti-inflammatory drug targets. Our project refines these compounds for schistosomiasis while assessing their efficacy in human inflammation models through rational design. Targeting the doorstop pocket may offer new therapeutic strategies in diseases where TrxR inhibition is beneficial.

- heterologous expression of protein and their purification- biocrystallography, cryo-EM- enzymology- protein-ligand bindingno other languages than English are requested

At present there are 1 assistant professor, one technician, 2 Ph.D student and 3 master students, which assure a young and active scientific environment in the lab.The group of Prof. Angelucci and Prof. Ardini is well-equipped with all the technologies and instrumentations for structural and functional studies of protein and is already involved in a structural genomics project on Schistosoma mansoni. We have monthly scheduled synchrotron time to collect X-ray high resolution data on protein crystals; we are also participating in a national consortium of universities to get access to cryo-electron microscopy (Cryo-EM) facilities present in Europe.