Caspases as therapeutic targets

Abstract

The development of small molecules to modulate caspase activity offers a novel therapeutic strategy in the treatment of apoptosis-related and inflammatory diseases. Caspases are key mediators of apoptosis and inflammation; deregulation of their activation or expression can lead to the development of conditions such as neurodegenerative and autoinflammatory disorders. This review details the different caspase-associated disorders while focusing on caspase-1 inhibition as a potential therapeutic strategy. Problems facing the development of effective and safe caspase therapeutics will also be addressed.

Caspases in apoptosis and beyond

“…Treatment of those patients with a natural decoy IL-1 molecule (IL1Ra) rapidly and dramatically decreases disease manifestations (Hawkins et al, 2003;Hoffman et al, 2004). Caspase-1 inhibitors are under clinical trials for the treatment of familial cold urticaria, rheumatoid arthritis and other autoinflammatory diseases (Howley and Fearnhead, 2008).…”

Sodium dependence of lysophosphatidylcholine-induced caspase-1 activity and reactive oxygen species generation

“…However, both IL-1␤ and IL-18 can exert their biological actions only following transformation from their biologically inactive precursors into mature, biologically active forms, which is mediated by the cysteine protease caspase-1 (Dinarello, 2009). It is, thus, not surprising that caspase-1 has been considered as a potential therapeutic target in various neurological diseases (Howley and Fearnhead, 2008;Chakraborty et al, 2010;Vezzani et al, 2010), and a large number of recently published articles has focussed on mechanisms regulating caspase-1 activity.…”

Regulation of NF-κB signaling by caspases and MALT1 paracaspase

“…The functional consequences of protein cleavage are mostly transient due to the dynamic exchange of uncleaved and cleaved proteins in the signaling complex and protein turnover in general. Several proteases control key steps in immune cell signaling and represent interesting targets for therapeutic immunomodulation [4,5]. In this context, caspases are a family of cysteine proteases that have attracted a lot of attention.…”