Elucidation of the a-Keto-Aldehyde Binding Mechanism: A Lead Structure Motif for Proteasome Inhibition
Angewandte Chemie, 2010, DOI: 10.1002/anie.201005488, published on 19.12.2010
The proteasome's participation in essential biological processes such as stress response, cell proliferation, apoptosis, and antigen presentation has been well established. It is, therefore, not surprising that academia and the pharmaceutical industry have made efforts to develop a range of small synthetic inhibitors against this proteolytic molecular machine (see Scheme SS1 in the Supporting Information for examples). An overall structural comparison of some wellcharacterized inhibitors implies that most of these compounds form a covalent bond with the N-terminal nucleophilic threonine (Thr1) located at the active sites in the two inner heptameric b rings of the 20S proteasome, termed b1, b2, and b5 according to the subunit of their origin.