**5.1.1 Peptide aldehydes**

140 Rheumatoid Arthritis – Treatment

In the nervous system, UPS is present in neurons, glia and synapses and regulates numerous functions including neuronal signalling, synapse assembly, maintenance, and function [Mengual et al., 1996]. Recent work utilizing the powerful genetic tools in *C. elegans* and *Drosophila* as well as synaptic assays in mammalian neuronal culture systems has unravelled the critical role of UPS in neuronal signaling. Active E3 ligases are identified at the synapse which participates in synaptic plasticity [Myat et al., 2002]. Moreover, localization of many E3 ligases in nucleus and synapse suggests the interplay between UPS regulation of transcriptional programs that function in synaptic modulation and local

UPS regulates synaptic functions by controlling levels of pre-synaptic proteins [Speese et al., 2003]. At the post-synaptic levels, the UPS regulates the surface expression and internalization of NMDA- and AMPA-glutamate receptors [Moriyoshi et al., 2004]. It has been implicated that mechanical allodynia and hyperalgesia can be prevented with NMDAreceptor antagonists [Laughlin et al., 1997**]**. During pathological pain UPS regulates neuronal signalling by controlling levels of synaptic proteins [Ossipov et al, 2007]. Much future work is needed to identify exact role of UPS in acute and chronic pain conditions.

Proteasome inhibitors are considered as a potential remedy for cancer, inflammation-related disorders and neurodegenerative diseases. Proteasome inhibitors can cause cellular apoptosis in proliferating cancer cells by affecting various short-lived proteins, resulting in inhibition of NF-ĸB activity, increased activity of p53 and Bax proteins, and accumulation of cyclin- dependent kinase inhibitors p27 and p21 [Moriyoshi et al., 2004; Van Waes et al., 2007]. Preclinical studies show that malignant, transformed, and proliferating cells are more susceptible to proteasome inhibition than cells in a resting state [Adams, 2002; Sherr, 1996]. Bortezomib is the first inhibitor of the ubiquitin-proteasome pathway to enter clinical studies [Adams et al., 1999; Richardson et al., 2003]. On the basis of a large, multicenter phase II clinical trial in which approximately one third of patients with advanced multiple myeloma (MM) had a significant response to therapy with bortezomib, on May 13th 2003, the US Food and Drug Administration granted approval for use of this drug in the treatment of patients with MM [Richardson et al., 2003]. The promising preclinical and clinical activity exhibited by bortezomib in MM and non-Hodgkin lymphomas (NHL) has confirmed the proteasome as a relevant and important target in the treatment of cancer. Several proteasome inhibitors

In the case of RA, up-regulation of the most important pro-inflammatory mediators such as TNF-α, IL-1β, IL-6, iNOS and endothelial cell adhesion molecules (e.g. vascular cell adhesion molecule 1 (VCAM-1)) are regulated by NF-κB [Van Waes et al., 2007; Han et al 1998]. Therefore RA qualifies as a potential target for proteasome inhibitors. *In vitro* and *in vivo* studies have presented encouraging results by the use of different proteasome

Proteasome inhibitors include a variety of natural and chemically synthesized molecules which exclusively inhibit proteasome activity. The structure and function of some important

are being tested and are in the pre-clinical and clinical phase of testing.

inhibitors to reduce the NF-κB activation.

classes of proteasome inhibitors are described here.

**5.1 Proteasome inhibitors** 

**4. UPS in neuronal signalling** 

synaptic regulation of protein degradation.

**5. Proteasome inhibition** 

Peptide aldehydes were the first proteasome inhibitors to be developed [Palombella et al., 1994; Rock et al., 1994]. These include MG132 (Z-Leu-Leu- Leucinal-) (Fig 5), MG115 (Z-Leu-Leu-norvalinal-) and calpain inhibitor I (*N*-acetyl-Leu-Leu-norleucinal). These compounds are potent, reversible and cell permeable. MG132 is a reversible inhibitor of the chymotrypsin like activity of the proteasome.
