**5.1.3 Lactacystin**

Lactacystin is a naturally occurring compound produced by *Streptomyces lactacystinaeus.* It selectively targets the β5 subunit of the proteasome [Fenteany et al., 1995] by covalent acylation of the amino-terminal threonine residues and is considered as an irreversible inhibitor of the proteasome. The active component of lactacystin is the highly reactive *clasto*lactacystin β-lactone and PS-519 (Fig 5).

Fig. 6. Structures of selected proteasome inhibitors [Elliott et al., 2003].

Proteasome Targeted Therapies in Rheumatoid Arthritis 143

Fig. 7. Effects of proteasome inhibitor MG132 on (A) arthritis index; severity of arthritis was scored using a macroscopic scoring system according to changes in erythema and oedema in each paw (B) NF-κB and p50 activation in arthritic ankle joint of AIA rat. (a) autoradiograph of electrophoretic mobility shift assay. The upper two bands represent NF-κB and p50 homodimer complexes (indicated by arrows), (b) and (c) semi-quantification of the NF-κB

MG132 treatment significantly down-regulated the expression of NF-κB1 (p50) in inflamed ankle joints as well as the DNA binding activity of both NF-κB and p50 homodimer in arthritic ankle joints (Fig 7 A and B). These results indicate that MG132 hinders the nuclear localization of NF-ĸB by retaining them in the cytosol in an inactive form bound to the inhibitory protein IκB, and also blocks UPS-mediated processing of the p105 precursor to

and (p50)2 levels.
