Selective Inhibition of the Immunoproteasome


Proteasomes are abundant and ubiquitous multi-protein complexes capable of degrading almost any protein into oligopeptides. The 20S proteasome is composed of 14 subunits (seven α and seven β) arranged in four rings to form a barrel, the ends of which can open to accept substrates. Catalytic activity is confined to three of the β-subunits, all of which are N-terminal threonine proteases. The addition of 19S regulatory complexes at the ends of the 20S multimer creates the 26S proteasome and confers the ability to process ubiquitylated substrates in an ATP-dependent manner.

Yeast 20S proteasome structureProteasomes chomp their way through a huge number of proteins including defective ribosomal products that arise from imperfections in the conversion of genetic information into proteins. The oligopeptides that result are then rapidly processed to constituent amino acids by endo- and amino-peptidases. Some oligopeptides, however, escape further processing and are presented on the cell surface by MHC Class I molecules. This provides a mechanism for the immune system to monitor the gene products that a particular cell is processing.

A variant of the proteasome, the immunoproteasome, is constitutively expressed in immune tissues and can be induced in other cell types in response to cytokines such as γ-interferon and TNF-α. The immunoproteasome differs from the proteasome at the level of the catalytic β-subunits and generates alternate peptides that modify the antigens presented by MHC class I.

The proteasome has been validated as a target in oncology and bortezomib was the first proteasome inhibitor approved in the US (2003). Until now, however, utility of proteasome inhibitors in auto-immune diseases has been hampered by the higher doses of conventional inhibitors required and the consequently smaller therapeutic window. This situation has potentially changed with results from Proteolix using their immunoproteasome-selective inhibitor, PR-957.

PR-957 is a peptide epoxy-ketone that selectively inhibits the LMP7 catalytic subunit of the immunoproteasome. Inhibition of this subunit modulates immune cell signalling and blocks production of cytokines associated with autoimmune inflammation, without affecting proteasome function in non-immune cells. In mouse models of rheumatoid arthritis, PR-957 treatment reversed signs of disease and reduced cellular infiltration, cytokine production and autoantibody levels. The study is published in the journal Nature Medicine.

Proteolix plans to file an Investigational New Drug Application for PR-957 in mid-2010.

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