Rational structure-based design of a novel carboxypeptidase R inhibitor.
Chem Biol
; 9(10): 1129-39, 2002 Oct.
Article
em En
| MEDLINE
| ID: mdl-12401497
ABSTRACT
A novel carboxypeptidase R (CPR) inhibitor, related to potato carboxypeptidase inhibitor (PCI), was designed using rational structure-based strategies, incorporating two principle facts CPR has a strong affinity for basic amino acids, and the two lysine and arginine residues of PCI are orientated in the same direction and held in close spatial proximity by three disulfide bonds. Initially, a disulfide-bonded fragment of PCI was synthesized showing weak competitive inhibitory activity against CPR. Subsequently, a smaller linear 9-mer peptide, designated CPI-2KR, was designed/synthesized and found to be a more efficient competitive inhibitor of CPR, without affecting the activity of the other plasma carboxypeptidase, carboxypeptidase N. In vitro studies showed that, together with tissue plasminogen activator, CPI-2KR synergistically accelerated fibrinolysis, representing a lead compound for the design of smaller organic molecules for use in thrombolytic therapy.
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Base de dados:
MEDLINE
Assunto principal:
Oligopeptídeos
/
Desenho de Fármacos
/
Carboxipeptidase B2
/
Inibidores Enzimáticos
Idioma:
En
Ano de publicação:
2002
Tipo de documento:
Article