Design of kallidin-releasing tissue kallikrein inhibitors based on the specificities of the enzyme's binding subsites

Design of kallidin-releasing tissue kallikrein inhibitors based on the specificities of the enzyme's binding subsites

Author Portaro, Fernanda Calheta Vieira Autor UNIFESP Google Scholar
Cezari, Maria Helena Sedenho Autor UNIFESP Google Scholar
Juliano, Maria Aparecida Autor UNIFESP Google Scholar
Juliano, Luiz Autor UNIFESP Google Scholar
Walmsley, Adrian R. Google Scholar
Prado, Eline Sant'Anna Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
UNIV SHEFFIELD
Abstract The tissue kallikrein inhibitors reported in the present work were derived by selectively replacing residues in N-alpha-substituted arginine- or phenylalanine-pNA (where pNA is p-nitroanilide), and in peptide substrates for these enzymes. Phenylacetyl-Arg-pNA was found to be an efficient inhibitor of human tissue kallikrein (K-i 0.4 mu M) and was neither a substrate nor an inhibitor of plasma kallikrein. The peptide inhibitors having phenylalanine as the P-1 residue behaved as specific inhibitors for kallidin-releasing tissue kallikreins, while plasma kallikrein showed high affinity for inhibitors containing (p-nitro)phenylalanine at the same position. The K-i value of the most potent inhibitor developed, Abz-Phe-Arg-Arg-Pro-Arg-EDDnp [where Abz is o-aminobenzoyl and EDDnp is N-(2,4-dinitrophenyl)ethylenediamine], was 0.08 mu M for human tissue kallikrein. Progress curve analyses of the inhibition of human tissue kallikrein by benzoyl-Arg-pNA and phenylacetyl-Phe-Ser-Arg-EDDnp indicated a single-step mechanism for reversible formation of the enzyme-inhibitor complex.
Language English
Date 1997-04-01
Published in Biochemical Journal. London: Portland Press, v. 323, n. 1, p. 167-171, 1997.
ISSN 0264-6021 (Sherpa/Romeo, impact factor)
Publisher Portland Press
Extent 167-171
Origin http://dx.doi.org/10.1042/bj3230167
Access rights Open access Open Access
Type Article
Web of Science ID WOS:A1997WR48800024
URI http://repositorio.unifesp.br/11600/42799

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