Design of kallidin-releasing tissue kallikrein inhibitors based on the specificities of the enzyme's binding subsites
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1997-04-01
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Portaro, Fernanda Calheta Vieira [UNIFESP]
Cezari, Maria Helena Sedenho [UNIFESP]
Juliano, Maria Aparecida [UNIFESP]
Juliano, Luiz [UNIFESP]
Walmsley, Adrian R.
Prado, Eline Sant'Anna [UNIFESP]
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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.
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Biochemical Journal. London: Portland Press, v. 323, n. 1, p. 167-171, 1997.