Cyclic, Linear, Cycloretro-Isomer, and Cycloretro-Inverso Peptides Derived from the C-Terminal Sequence of Bradykinin as Substrates or Inhibitors of Serine and Cysteine Proteases

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Lima, Aurelio Resende [UNIFESP]
Juliano, Luiz [UNIFESP]
Juliano, Maria Aparecida [UNIFESP]
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We investigated the inhibition of trypsin, human tissue (hK1) and human plasma kallikrein (HuPK), papain, and cathepsin L, B, and X by synthetic cyclic, cycloretro-isomer, cycloretro-inverso, and linear peptides derived from the C-terminal sequence of bradykinin. c(FSPFRG) and Ac-FSPFRG-NH(2) were taken as the references for cyclic and linear peptides, respectively. Longer and more flexible analogs of them with addition of 2, 3, or 4 Gly and cycloretro-isomer and cycloretro-inverso analogs of c(FSPFRG) and c(GGGFSPFRG) were obtained and assayed. the susceptibility to hydrolysis of the peptides to all proteases was also examined. the highest affinities were found for c(FSPFRG) with hK1, Ac-GGFSPFRG-NH(2) with HuPK, and psi (NHCO) c(fspfrG) with cathepsin L. the K(i) values for cathepsin B and X with cyclic peptides were lower than those of linear peptides. the serine proteases hydrolyzed all linear and cyclic peptides, except c(FSPFRG) and c(GFSPFRG). the cysteine proteases hydrolyzed only the linear peptides, which were poor substrates. Although the K(i) values obtained in the current work were in the mu M range, the cyclic and cycloretro-inverso peptides seem to be a promising approach to develop efficient and resistant to hydrolysis inhibitors for the kallikreins and lysosomal cysteine proteases.
Protein Journal. New York: Springer, v. 23, n. 4, p. 287-294, 2004.