From lysosomes to cells, from cells to Leishmania: amino acid esters as potential chemotherapeutic agents.
Amino acid esters can disrupt lysosomes and damage monocytes and certain lymphocyte populations. Lysosomal disruption involves pH trapping of the esters, followed by their hydrolysis by as yet unidentified enzymes. Accumulation of the more polar amino acids is assumed to cause osmotic lysis of the organelles. We have discovered that certain amino acid esters and amides destroy Leishmania mexicana amazonensis amastigotes lodged within macrophages in culture, as well as parasites isolated from mouse lesions. This paper reviews the amino acid specificity of parasite killing, the resistance of amastigotes derived from infection of macrophages with promastigotes, the involvement of an acidified compartment within the parasites, and the protection conferred by other amino acid esters, and by the protease inhibitors antipain and chymostatin, against the destruction of amastigotes by Leucine-methyl ester. Studies with tritiated esters confirm the critical role of ester hydrolysis for leishmanicidal activity and strengthen the view that similar mechanisms underlie disruption of lysosomes and destruction of Leishmania. Characterization of the parasite organelles and of the enzymes involved in the leishmanicidal activity as well as structure-activity studies may permit the design of compounds more selective for the parasites.
Rabinovitch
M
M
Unité d'Immunoparasitologie, Institut Pasteur, Paris, France.
Alfieri
S C
SC
D000818:Animals; D004151:Dipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D007894:Leishmania mexicana / Q000187:drug effects* / Q000201:enzymology; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D008247:Lysosomes / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
D004151:Dipeptides; D011480:Protease Inhibitors; C030365:leucine methyl ester; D007930:Leucine