Amino acids and peptides. XXII. Synthesis of substrates and inhibitors of human leukocyte cathepsin G.

Okada, Yoshio; Tsuda, Yuko; Teno, Naoki; Nagamatsu, Yoko; Okamoto, Utako

doi:10.1248/cpb.36.4794

Cited by 3 publications

(1 citation statement)

References 3 publications

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“…Table I shows the residue combinations which constitute the most probable primary cleavage sites in proteins for cathepsins B, L, and D as well as those residue combinations that are non-substrates for the enzymes. The data were derived from the literature [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] on the substrate specificity of the three enzymes.…”

Section: Methodsmentioning

confidence: 99%

T‐Helper‐Cell Determinants in Protein Antigens are Preferentially Located in Cysteine‐Rich Antigen Segments Resistant to Proteolytic Cleavage by Cathepsin B, L, and D

et al. 1991

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We report on a computer algorithm capable of predicting the location of T-helper-cell epitopes in protein antigen (Ag) by analysing the Ag amino acid sequence. The algorithm was constructed with the aim of identifying segments in Ag which are resistant to proteolytic degradation by the enzymes cathepsin B, L, and D. These are prominent enzymes in the endocytic pathway through which soluble protein Ag enter APC, and resistant segments in Ag may, therefore, be expected to contain more T-cell determinants than susceptible segments. From information available in the literature on the substrate specificity of the three enzymes, it is clear that a cysteine is not accepted in any of the S2, S1, S1', and S2' subsites of cathepsin B and L, and not in the S1 and S1' subsites of cathepsin D. Moreover, we have noticed that cysteine-containing T-cell determinants in a number of protein Ag are particularly rich in the amino acids alanine, glycine, lysine, leucine, serine, threonine, and valine. By searching protein Ag for clusters of amino acids containing cysteine and two of the other amino acids we were able to predict 17 out of 23 empirically known T-cell determinants in the Ag with a relatively low number of false (positive) predictions. Furthermore, we present a new principle for searching Ag for potential amphipatic alpha-helical protein segments. Such segments accord well with empirically known T-cell determinants and our algorithm produces a lower number of false positive predictions than the principle based on discrete Fourier transformations previously described.

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Section: Methodsmentioning

confidence: 99%

T‐Helper‐Cell Determinants in Protein Antigens are Preferentially Located in Cysteine‐Rich Antigen Segments Resistant to Proteolytic Cleavage by Cathepsin B, L, and D

et al. 1991

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Synthetic Inhibitors of Elastase

Edwards

Bernstein

1994

Medicinal Research Reviews

215

156

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For more than two decades investigators around the world, in both academic and industrial institutions, have been developing inhibitors of human neutrophil elastase. A number of very elegant and insightful strategies have been reported. In the case of reversible peptidic inhibitors, this has resulted in the identification of some extremely potent compounds with dissociation constants in the 10(-11) M range. This is quite an accomplishment considering that these low molecular-weight inhibitors are only tri- and tetrapeptides. In the case of the heterocyclic-based inhibitors, the challenge of balancing the heterocycle's inherent reactivity and aqueous stability with the stability of the enzyme-inhibitor adduct has been meet by either using a latent, reactive functionality which is only activated within the enzyme, or by incorporating features which selectively obstruct deacylation but have little effect on the enzyme acylation step. The underlying goal of this research has been the identification of agents to treat diseases associated with HNE. Several animal models have been developed for evaluating the in vivo activity of elastase inhibitors, and compounds have been shown to be effective in all of these models by the intravenous, intratrachael or oral routes of administration. However, only a very small percentage of compounds have possessed all the necessary properties, including lack of toxicity, for progression into the clinic. The peptidyl TFMK ICI 200,880 (25-12) has many of the desired characteristics of a drug to treat the diseases associated with HNE: chemical stability, in vitro and in vivo activity, a long duration of action, and adequate metabolic stability. Currently ICI 200,880 is the only low molecular-weight HNE inhibitor known to be undergoing clinical trials, and may be the compound which finally demonstrates the clinical utility of a synthetic HNE inhibitor.

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A Molecular Probe with Both Chromogenic and Fluorescent Units for Detecting Serine Proteases

et al. 2021

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A molecular probe with l-phenylalanine p-nitroanilide and l-lysin 4-methylcoumaryl-7-amide, in which these amino acid derivatives are connected through a succinic-acid spacer, was prepared. Trypsin and papain were detected by blue-fluorescence emission of generated 7-amino-4-methylcoumarin (AMC). α-Chymotrypsin and nattokinase were detected from both the blue-fluorescence emission of AMC and the UV absorbance of p-nitroaniline. In addition, different time courses of p-nitroaniline and AMC were observed between the reaction of P1 with α-chymotrypsin and that with nattokinase. In the case of nattokinase, both the fluorescence emission and UV absorbance slowly increased. In contrast, the increasing UV absorbance was saturated at the early stage of the reaction of the present probe with chymotrypsin, whereas the fluorescence emission continuously increased in the following stages.

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Amino acids and peptides. XXII. Synthesis of substrates and inhibitors of human leukocyte cathepsin G.

Cited by 3 publications

References 3 publications

T‐Helper‐Cell Determinants in Protein Antigens are Preferentially Located in Cysteine‐Rich Antigen Segments Resistant to Proteolytic Cleavage by Cathepsin B, L, and D

T‐Helper‐Cell Determinants in Protein Antigens are Preferentially Located in Cysteine‐Rich Antigen Segments Resistant to Proteolytic Cleavage by Cathepsin B, L, and D

Synthetic Inhibitors of Elastase

A Molecular Probe with Both Chromogenic and Fluorescent Units for Detecting Serine Proteases

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