The Design of Cysteine Proteases Inhibitors

Terry Hart

Peakdale Molecular Ltd

Peakdale Science Park

Sheffield Road

Chapel-en-le-Frith

High Peak  SK23 0PG

The three major families of cysteine proteases, the papain-like, the caspases and the picornaviral families, represent, perhaps, the most ubiquitous enzyme class found in nature. They have a vital role in all aspects of cell function, including cell death, immune function and the inflammatory response, tissue and bone remodelling and also affect the virulence of most infectious diseases.

Of the four major classes of proteases, historically it has been far more difficult to design drugs that act as inhibitors of cysteine proteases. This drug design problem is largely due to the drug targeting of the highly reactive thiol, which is essential for the normal catalytic hydrolysis of amide bonds, but which makes selectivity and the avoidance of idiosyncratic reactions key drug design issues.  

Structure based drug design has been used to design potent and selective inhibitors, but the first generation drugs that progressed through the pipeline have had less than optimal pharmaceutical properties. Now a new generation of inhibitor drugs is emerging and this overview will focus on the latest developments in the drug design of orally bioavailable cysteine protease inhibitors with particular reference to Interleukin converting enzyme (ICE), Cathepsin K and Cathepsin S.