pH Dependence of inhibitors targeting the occluding loop of cathepsin B

✍ Scribed by Brian E Cathers; Cynthia Barrett; James T Palmer; Robert M Rydzewski

• Book ID: 104266467
• Publisher: Elsevier Science
• Year: 2002
• Tongue: English
• Weight: 152 KB
• Volume: 30
• Category: Article
• ISSN: 0045-2068
• DOI: 10.1016/s0045-2068(02)00009-3

✦ Synopsis

Potent and selective cathepsin B inhibitors have previously been synthesized based upon the natural product cysteine protease inhibitor E-64. X-ray crystal data indicates that these compounds interact through their free carboxylate with the positively charged histidine residues located on the prime-side of the active site within the occluding loop of cathepsin B. Herein, we examine the pH dependence of two prime-side-binding compounds. In each case there is a dramatic decrease in k(inact)/K(I) as the pH is raised from 4 to 7.8 corresponding to a single ionization of pK(a) 4.4. These results suggest that targeting of the occluding loop of cathepsin B may be a poor inhibitor design strategy if the enzyme environment has a pH greater than 5.5. However, this type of inhibitor may be a useful tool to help elucidate the role and the environment of cathepsin B in invading tumors.