Characterization of the peptide substrate specificity of glutathionylspermidine synthetase from Crithidia fasciculata

Craecker, Sofie De; Verbruggen, Christophe; Rajan, Padinchare; Smith, Kelvin E.; Haemers, Achiel; Fairlamb, Alan H.

doi:10.1016/s0166-6851(96)02778-8

Cited by 23 publications

(30 citation statements)

References 21 publications

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“…[21][22][23] Modified γ-glutamyl peptides composed of non-proteinogenic amino acids, Damino acids, α-hydoxy acids, etc. were then screened using the CaSR assay as an index.…”

Section: Structure-casr-activity Relation Of Kokumi γ-Glutamyl Peptidesmentioning

confidence: 99%

Structure–CaSR–Activity Relation of <i>Kokumi</i> γ-Glutamyl Peptides

et al. 2016

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Modulation of the calcium sensing receptor (CaSR) is one of the physiological activities of γ-glutamyl peptides such as glutathione (γ-glutamylcysteinylglycine). γ-Glutamyl peptides also possess a flavoring effect, i.e., sensory activity of kokumi substances, which modifies the five basic tastes when added to food. These activities have been shown to be positively correlated, suggesting that kokumi γ-glutamyl peptides are perceived through CaSRs in humans. Our research is based on the hypothesis that the discovery of highly active CaSR agonist peptides will lead to the creation of practical kokumi peptides. Through continuous study of the structure-CaSR-activity relation of a large number of γ-glutamyl peptides, we have determined that the structural requirements for intense CaSR activity of γ-glutamyl peptides are as follows: existence of an N-terminal γ-L-glutamyl residue; existence of a moderately sized, aliphatic, neutral substituent at the second residue in an L-configuration; and existence of a C-terminal carboxylic acid, preferably with the existence of glycine as the third constituent. By the sensory analysis of γ-glutamyl peptides selected by screening using the CaSR activity assay, γ-glutamylvalylglycine was found to be a potent kokumi peptide. Furthermore, norvaline-containing γ-glutamyl peptides, i.e., γ-glutamylnorvalylglycine and γ-glutamylnorvaline, possessed excellent sensory activity of kokumi substances. A novel, practical industrial synthesis of regiospecific γ-glutamyl peptides is also required for their commercialization, which was achieved through the ring opening reaction of N-α-carbobenzoxy-L-glutamic anhydride and amino acids or peptides in the presence of Nhydroxysuccinimide.

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“…[21][22][23] Modified γ-glutamyl peptides composed of non-proteinogenic amino acids, Damino acids, α-hydoxy acids, etc. were then screened using the CaSR assay as an index.…”

Section: Structure-casr-activity Relation Of Kokumi γ-Glutamyl Peptidesmentioning

confidence: 99%

Structure–CaSR–Activity Relation of <i>Kokumi</i> γ-Glutamyl Peptides

et al. 2016

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“…Despite the successful inhibition of enzymes such as trypanothione reductase 6 and glutathionylspermidine synthetase 7,8 in situ, some of these compounds have proved to be inactive against trypanosomes in vitro. [6][7][8] The poor success of rational drug design studies to produce compounds active in vitro against these types of protozoa led us to adopt a lead directed approach to identify potential antiparasitic compounds. In a recent paper 9 we reported the identification of several glutathione derivatives with activity against Trypanosoma and Leishmania.…”

Section: Introductionmentioning

confidence: 99%

QSAR Study on the Contribution of Log P and E_s to the in Vitro Antiprotozoal Activity of Glutathione Derivatives

Daunes¹,

D’Silva²,

Kendrick³

et al. 2001

J. Med. Chem.

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A series of N-S-blocked glutathione monoester and diester derivatives based on N-benzyloxycarbonyl-S-(2,4-dinitrophenyl)glutathione were evaluated for activity against the pathogenic parasites Trypanosoma brucei brucei, Trypanosoma cruzi, and Leishmania donovani in vitro.Only monoesters 7-9 with a log P value of >2.7 were active inhibitors of T.b. brucei bloodstream form trypomastigotes. Diester compounds 10-15 and 17-27 in most cases were better inhibitors of T.b. brucei than monoester compounds, and some displayed high activity against T. cruzi 14 and L. donovani 17, 19, 29. Compounds 14, 24, and 25 were the most active compounds identified against T.b. brucei having ED(50) values of <0.4 microM. Analysis of the inhibition data (ED(50)) vs calculated log P and E(s) values provided evidence to support membrane penetration and steric factors as the key component in the activity of these compounds. The optimum values for log P and E(s) determined were 5.8 and -0.70, respectively. A QSAR equation relating log(1/ED(50)) vs log P and E(s) was determined and interpreted within the proposed mechanism of activity for these compounds.

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“…The preparation of compounds 14 and 15 has been reported but no experimental procedures nor spectroscopic data were depicted. 26,29 , and 30) were devoid of inhibitory action towards T. cruzi proliferation at concentrations up to 20 µg/ml. The lack of biological activity is extremely surprising bearing in mind the structural likeness between the tested drugs and the chemical structures of the lead drugs such as 7-12.…”

Section: Resultsmentioning

confidence: 97%

“…For example, it has been found that analogues of glutathione in which the cisteine residue was replaced by isoleucine to form L-γ-Glu-L-Ile-Gly (compound 5) or L-γ-Glu-L-Ile-L-Ala (compound 6) exhibited a non-competitive inhibition with K i at the low milimolar range. 26 Phosphonates and phosphinates are well known inhibitors of C:N-ligases. 27,28 This findings have led to the design of interesting phosphorous-containing drugs that behave as inhibitors of the enzymatic activity of GSS.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of glutathione-like tripeptides against Trypanosoma cruzi

Ravaschino¹,

Docampo²,

Rodríguez

2003

Arkivoc

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Glutathionylspermidine synthase (GSS) is a crucial enzyme in the trypanothione biosynthetic pathway and is also an interesting molecular target for drug design. We synthesized a series of amides of a glutathione analogue (L-γ-Glu-L-Leu-Gly-NHR) where R are linear alkyl groups. All of these drugs exhibited marginal biological activity against the responsible agent of Chagas' disease, the protozoan Trypanosoma cruzi.

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Characterization of the peptide substrate specificity of glutathionylspermidine synthetase from Crithidia fasciculata

Cited by 23 publications

References 21 publications

Structure–CaSR–Activity Relation of <i>Kokumi</i> γ-Glutamyl Peptides

Structure–CaSR–Activity Relation of <i>Kokumi</i> γ-Glutamyl Peptides

QSAR Study on the Contribution of Log P and E_s to the in Vitro Antiprotozoal Activity of Glutathione Derivatives

Synthesis and biological evaluation of glutathione-like tripeptides against Trypanosoma cruzi

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Characterization of the peptide substrate specificity of glutathionylspermidine synthetase from Crithidia fasciculata

Cited by 23 publications

References 21 publications

Structure–CaSR–Activity Relation of <i>Kokumi</i> γ-Glutamyl Peptides

Structure–CaSR–Activity Relation of <i>Kokumi</i> γ-Glutamyl Peptides

QSAR Study on the Contribution of Log P and Es to the in Vitro Antiprotozoal Activity of Glutathione Derivatives

Synthesis and biological evaluation of glutathione-like tripeptides against Trypanosoma cruzi

Contact Info

Product

Resources

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QSAR Study on the Contribution of Log P and E_s to the in Vitro Antiprotozoal Activity of Glutathione Derivatives