Schematic representation of the discovery and development of novel inhibitors of the immunoproteasome Image by Martina Gobec
Publish Date: 05.12.2016
Category: Outstanding research achievements, Interdisciplinary research, Our contribution to sustainable development goals
Sustainable development goals: 3 Good health and well-being (Indicators)
Researchers from the Faculty of Pharmacy of the University of Ljubljana discovered new possibilities for the treatment of autoimmune and inflammatory conditions and cancer by preparing small nonpeptidic molecules that inhibit the immunoproteasome enzyme.
Authors: Izidor Sosič, Martina Gobec, Boris Brus, Damijan Knez, Matej Živec, Aleš Obreza, Irena Mlinarič-Raščan, Stanislav Gobec
Immunoproteasome is the enzyme whose elevated expression and more expressed activity are associated with numerous autoimmune and inflammatory diseases, as well as different types of cancer. The findings show that inhibiting its activity indicated a promising therapeutic approach. The majority of known immunoproteasome inhibitors are peptidic in nature. Low bioavailability and poor metabolic stability are characteristics of these structural types of compounds.
The researchers from the Faculty of Pharmacy of the University of Ljubljana (Izidor Sosič, Martina Gobec, Boris Brus, Damijan Knez, Matej Živec, Aleš Obreza, Irena Mlinarič-Raščan, Stanislav Gobec) and their colleagues from the National Institute of Chemistry (Janez Konc, Samo Lešnik, Mitja Ogrizek), the Department for Environmental Studies at the Jožef Stefan Institute (Dušan Žigon) and the Faculty of Mathematics, Natural Sciences and Informational Technologies of the University of Primorska (Dušanka Janežič) used virtual screening and subsequent chemical optimization to prepare new compounds with nonpeptidic base structures. The newly discovered compounds selectively inhibit the chymotrypsin-like (β5i) activity of immunoproteasome, while their effect on the remaining subunits of the immunoproteasome and on the constitutive (standard) proteasome is negligible. The researchers showed that selective inhibition of immunoproteasome can also be achieved by using molecules without peptidic structure. In addition to the previously mentioned greater stability, the nonpeptidic molecules also cover a greater chemical space. These are the reasons why the described inhibitors represent an excellent foundation for the development of compounds with additionally improved physico-chemical properties and a more selective impact on immunoproteasome.
Source: SOSIČ, Izidor, GOBEC, Martina, BRUS, Boris, KNEZ, Damijan, ŽIVEC, Matej, KONC, Janez, LEŠNIK, Samo, OGRIZEK, Mitja, OBREZA, Aleš, ŽIGON, Dušan, JANEŽIČ, Dušanka, MLINARIČ-RAŠČAN, Irena, GOBEC, Stanislav. Nonpeptidic selective inhibitors of the chymotrypsin-like (β5i) subunit of the immunoproteasome. Angewandte Chemie International Edition 2016, 55, 5745-5748.
Schematic representation of the discovery and development of novel inhibitors of the immunoproteasome Image by Martina Gobec