Research

Identification of non-peptidic inhibitors of the immunoproteasome using fragment based drug discovery methods

Code:

N1-0068

Range:

01. November 2017 - 31. October 2020

Range:

0,56 FTE

Leader:

Stanislav Gobec

Field:

1-09 Natural sciences and Mathematics - Pharmacy

Abstract:

The proteasome is an intracellular protease that represents a vital part of the ubiquitin-proteasome system. It degrades a wide range of proteins and has critical functions in many biological processes including cell cycle control, apoptosis, inflammation, and signal transduction. The constitutive isoform (cCP) of the proteasome is expressed in all eukaryotic cells while its immunomodulatory isoform, the immunoproteasome (iCP) is mainly expressed in cells associated with the immune system. Notably, the expression of the iCP can be induced in non-immune tissues by pro-inflammatory cytokines. Dysregulation of the proteasomes is known to lead to the development of diverse diseases, such as malignancies, autoimmune and inflammatory diseases. The latest research shows that selective inhibition of the iCP has great potential as a novel approach for the treatment of inflammatory diseases and a wide range of autoimmune disorders. So far, the known inhibitors of the iCP encompass compounds of peptidic type that are prone to poor metabolic stability and low bioavailability. The main objective of the proposed Project is to use a fragment based approach to identify non-peptidic compounds of both non-covalent and covalent nature that will selectively inhibit the beta5i subunit of the iCP, its most important subunit.