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The anti-leishmanial activity of dipeptide esters on Leishmania amazonensis amastigotes

Published online by Cambridge University Press:  06 April 2009

C. Ramazeilles ,
L. Juliano ,
J. R. Chagas  and
M. Rabinovitch
C. Ramazeilles
Affiliation:
Unité d'Immunoparasitologie, Institut Pasteur, and Centre National de Ia Recherche Scientifique (A040361), 25 rue du Docteur Roux, 75724 Paris, France
L. Juliano
Affiliation:
Department de Biofisica, Escola Paulista de Medicina, Rua 3 de Maio 100, 04044 São Paulo SP, Brazil
J. R. Chagas
Affiliation:
Department de Biofisica, Escola Paulista de Medicina, Rua 3 de Maio 100, 04044 São Paulo SP, Brazil
M. Rabinovitch
Affiliation:
Unité d'Immunoparasitologie, Institut Pasteur, and Centre National de Ia Recherche Scientifique (A040361), 25 rue du Docteur Roux, 75724 Paris, France
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Summary

L-Amino acid esters, such as L-Leu-OMe, kill Leishmania amazonensis amastigotes by a mechanism which appears to involve ester hydrolysis by cysteine proteinases located in the parasite megasomes. We have examined the killing of isolated amastigotes by L-dipeptide esters and derived some structure-activity correlations. Toxicity of the compounds for the parasites was measured by a tetrazolium (MTT) reduction assay. The results show that active dipeptide esters contained at least I hydrophobic amino acid (Leu, Ile, Val, Phe or Trp). The activity of homodipeptide methyl esters depended on the nature of the amino acid, as indicated by the following series: Phe-Phe-OMe < Val-Val-OMe < Leu-Leu-OMe < Trp-Trp-OMe < Ile-Ile-OMe. The nature of the amino acids in Leu-X-OMe and X-Leu-OMe was relatively unimportant when X was Phe, Trp or Val. However, when X was Ala or Gly, Leu-X-OMe was several-fold more active than X-Leu-OMe.

Keywords

Leishmania amazonensisamastigotesdipeptide esters
Type
Research Article
Information
Parasitology , Volume 100 , Issue 2 , April 1990 , pp. 201 - 207
Copyright
Copyright © Cambridge University Press 1990

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References

Alfieri, S. C., Ramazeilles, C., Zilberfarb, V., Galpin, I., Norman, S. E. & Rabinovitch, M. (1988). Proteinase inhibitors protect Leishmania amazonensis amastigotes from destruction by amino acid esters. Molecular and Biochemical Parasitology 29, 191–201.CrossRefGoogle ScholarPubMed
Alfieri, S. C., Shaw, E., Zilberfarb, V. & Rabinovitch, M. (1989). Leishmania amazonensis: involvement of cysteine proteinases in the killing of isolated amastigotes by L-leucine methyl ester. Experimental Parasitology 68, 423–31.CrossRefGoogle ScholarPubMed
Antoine, J. C., Jouanne, C. & Ryter, A. (1989). Megasomes are the target of leucine methyl ester in Leishmania amazonensis amastigotes. Parasitology 99, 1–9.CrossRefGoogle ScholarPubMed
Borrebaeck, C. A. K., Danielsson, L. & Möller, S. A. (1988). Human monoclonal antibodies produced by primary in vitro immunization of peripheral blood lymphocytes. Proceedings of the National Academy of Sciences, USA 85, 3995–9.CrossRefGoogle ScholarPubMed
Chorev, M. & Goodman, M. (1983). Partially modified retro-inverso peptides. International Journal of Peptide and Protein Research 21, 258–68.CrossRefGoogle ScholarPubMed
Degrado, W. F. (1988). Design of peptides and proteins. Advances in Protein Chemistry 39, 51–124.CrossRefGoogle ScholarPubMed
Fauchère, J. L. & Plĭska, V. (1983). Hydrophobic parameters of amino-acid side chains from the partitioning of N-acetyl-amino acid amides. European Journal of Medicinal Chemistry 18, 369–75.Google Scholar
Goldman, R. & Naider, F. (1974). Permeation and stereospecificity of hydrolysis of peptide esters within intact lysosomes in vitro. Biochimica et Biophysica Acta 338, 224–33.CrossRefGoogle Scholar
Juliano, M. A. & Juliano, L. (1985). Synthesis and kinetic parameters of hydrolysis by trypsin of some acyl-arginyl-p-nitroanilides and peptides containing arginyl-p-nitroanilide. Brazilian Journal of Medical and Biological Research 18, 435–45.Google ScholarPubMed
Pupkis, M. F. & Coombs, G. H. (1984). Purification and characterization of proteolytic enzymes of Leishmania mexicana mexicana amastigotes and promastigotes. Journal of General Microbiology 130, 2375–83.Google Scholar
Pupkis, M. F., Tetley, L. & Coombs, G. H. (1986). Leishmania mexicana: amastigote hydrolases inunusual lysosomes. Experimental Parasitology 62, 29–39.CrossRefGoogle ScholarPubMed
Rabinovitch, M. (1989). Leishmanicidal activity of amino acid and peptide esters. Parasitology Today 5, 299–304.CrossRefGoogle ScholarPubMed
Rabinovitch, M. & Alfieri, S. C. (1987). From lysosomes to cells, from cells to Leishmania: amino acid esters as potential chemotherapeutic agents. Brazilian Journal of Medical and Biological Research 20, 665–74.Google ScholarPubMed
Rabinovitch, M. & Zilberfarb, V. (1988). Destruction of intracellular and isolated Leishmania mexicana amazonensis by amino acid amides. Parasitology 96, 289–96.CrossRefGoogle ScholarPubMed
Ramazeilles, C. & Rabinovitch, M. (1989). Leishmania amazonensis: uptake and hydrolysis of 3H-amino acid methyl esters by isolated amastigotes. Experimental Parasitology 68, 135–43.CrossRefGoogle ScholarPubMed
Ransom, J. T. & Reeves, J. P. (1983). Accumulation of amino acids within intracellular lysosomes of rat polymorphonuclear leukocytes incubated with amino acid methyl esters. Journal of Biological Chemistry 258, 9270–5.CrossRefGoogle ScholarPubMed
Steinherz, R., Tietze, F., Raiford, D., Gahl, W. & Schulman, J.D. (1982). Patterns of amino acid efflux from isolated normal and cystinotic human leukocyte lysosomes. Journal of Biological Chemistry 257, 6041–9.CrossRefGoogle Scholar
Thiele, D. L. & Lipsky, P. E. (1985). Regulation of cellular function by products of lysosomal enzyme activity: elimination of human natural killer cells by a dipeptide methyl ester generated from L-leucine methyl ester by monocytes and polymorphonuclear leukocytes. Proceedings of the National Academy of Sciences, USA 82, 2468–72.CrossRefGoogle ScholarPubMed
Thiele, D. L.Lispky, P. E. (1986). The immunosuppressive activity of L-leucyl-L-leucine methyl ester: selective ablation of cytotoxic lymphocytes and monocytes. Journal of Immunology 136, 1038–48.CrossRefGoogle ScholarPubMed