NEWS
New Journal of Peptide Science cover highlights persisting challenge of selective proteasome inhibition
The cover of Journal of Peptide Science will change when Issue 15:2 is published later this year.
This issue will announce the publication of a review entitled "The persisting challenge of selective and specific proteasome inhibition".
In this review, Luis Moroder (Editor-in-Chief of the Journal of Peptide Science), Robert Huber (Nobel Prize for Chemistry in 1988) and Michael Groll highlight the ongoing challenge for proteasome inhibition.
As soon as the review is published, you will be able to download it from the EPS website.
In the introduction the authors write:
In eukaryotic cells, most cytosolic and nuclear proteins are degraded by the ubiquitin–proteasome pathway, which is responsible for protein quality control, antigen processing, signal transduction, cell-cycle control, cell differentiation, and apoptosis. As protein homeostasis is critically involved in cancer cell survival, targeting the balance between production and destruction of proteins that mediate proliferation and other key factors of malignancy has advanced to a major focus of cancer research. Accordingly, the proteasome has emerged as a promising target for cancer therapy, and this therapeutic approach has recently been validated with the peptide boronate, bortezomib (VELCADE) . Indeed, for patients with multiple myeloma (MM), the peptide boronate exhibits unmatched antitumor activity, though not free of side effects. Thus, the development of new generations of proteasome inhibitors as anti-cancer drugs still remains a challenge.
The executioner of the ubiquitin–proteasome pathway is the 26S proteasome, which is built up from the 700 000 Da proteolytic core particle (20S proteasome) and two 900 000 Da regulatory particles (19S regulatory complex). The 20S proteasome has a cylindrical shape showing two-fold symmetry and containing multiple catalytic centres located within the inner cavity of a molecular cage. It comprises 28 subunits, which are arranged in four seven-membered rings that stack upon each other, yielding an α1–7β1–7β1–7α1–7 complex. Compared to archaebacterial proteasomes, which have 14 identical, and thus, 14 proteolytically active sites [12], eukaryotic proteasomes contain only three proteolytically active β subunits per β ring (subunits β1, β2, and β3), whereas the other β subunits are inactive.
The first class of proteasome inhibitors were the tripeptide aldehydes calpain inhibitor I (Ac-Leu-Leu-Nle-H) and leupeptin from actinomycete (Ac-Leu-Leu-Arg-H). Structural analysis of these inhibitors revealed the mechanism of protein degradation catalysed by the nucleophilic N-terminal threonine hydroxyl group (Thr1Oγ ) and led to structural characterization of the substrate-binding pockets of the caspase-like (β1 subunit), trypsinlike (β2 subunit), and chymotrypsin-like (β5 subunit) catalytic sites. Peptide aldehydes were shown to form reversible covalent hemiacetals with the Thr1Oγ. Analysis of diverse other functional electrophiles such as boronates, vinyl sulfones, and natural product-based α_, β_-epoxyketones provided additional insights into their various binding modes to the proteasomal active sites as well as into their ability to inhibit the different proteolytic activities of the proteasome.
