Abstract
The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. Selective inhibition of its catalytic activities is therefore a viable approach for the treatment of these diseases. However, the development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. We previously reported 7H-furo[3,2-g]chromen-7-one (psoralen)-based compounds with an oxathiazolone warhead as selective inhibitors of the chymotrypsin-like (β5i) subunit of immunoproteasome. Here, we describe the influence of the electrophilic warhead variations at position 3 of the psoralen core on the inhibitory potencies. Despite mapping the chemical space with different warheads, all compounds showed decreased inhibition of the β5i subunit of immunoproteasome in comparison to the parent oxathiazolone-based compound. Although suboptimal, these results provide crucial information about structure–activity relationships that will serve as guidance for the further design of (immuno)proteasome inhibitors.
Highlights
In mammals, most intracellular proteins are destined for degradation, which involves the proteasome, a multiprotease complex [1,2,3]
There are three individual core particle (CP) types: the constitutive proteasome, which is expressed in all eukaryotic cells, the thymoproteasome [11], which is exclusive to cortical thymic epithelial cells, and the immunoproteasome [12], which is expressed in cells of hematopoietic origin, but can be induced in other tissues
Recently, we discovered non-peptidic and β5i-selective inhibitors with a central psowe already determined that acrylamides and nitrile-based warheads led to worse inhibition ralen core [39]
Summary
Most intracellular proteins are destined for degradation, which involves the proteasome, a multiprotease complex [1,2,3]. The 26S proteasome represents the heart of the ubiquitin-proteasome system that is responsible for the maintenance of protein homeostasis and the regulation of various cellular processes [4,5,6]. It is a nucleophilic hydrolase with N-terminal Thr acting as a nucleophile to cleave the peptide bond of proteins [7]. The two outer α rings provide structural integrity and act like “gates” allowing the entry of unfolded proteins to the two inner β rings, which contain three catalytically active subunits responsible for proteolysis of substrates [8]. There are three individual CP types: the constitutive proteasome (cCP), which is expressed in all eukaryotic cells, the thymoproteasome (tCP) [11], which is exclusive to cortical thymic epithelial cells, and the immunoproteasome (iCP) [12], which is expressed in cells of hematopoietic origin, but can be induced in other tissues
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