pH Dependence of inhibitors targeting the occluding loop of cathepsin B.
Bioorg Chem
; 30(4): 264-75, 2002 Aug.
Article
em En
| MEDLINE
| ID: mdl-12392705
ABSTRACT
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Catepsina B
/
Inibidores de Cisteína Proteinase
/
Leucina
Limite:
Humans
Idioma:
En
Ano de publicação:
2002
Tipo de documento:
Article