From Lysosomes to Cells, From Cells to Leishmania: Amino Acid Esters, Potential Chemotherapeutic Agents?
Amino acid esters are weak bases, with pKs between 7 and 8, which, in their non-protonated species, easily permeate through cell membranes. Similar to other weak bases such as methylamine or chloroquine, the esters can be trapped by protonation within the acidified milieu of lysosomes (de Duve et al., 1974). However, amino acid esters are not only trapped but also hydrolyzed by as yet uncharacterized lysosomal enzymes. Lysosomal accumulation of the more charged, and thus, less permeant amino acids, may result in osmotic swelling and disruption of the organelles (Goldman and Kaplan, 1973; Reeves, 1979). Possibly related to the lysosomal effects, certain amino acid and dipeptide esters have been shown to be selectively toxic to mammalian cells (Thiele et al., 1983; Thiele and Lipsky, 1985, 1986). This selectivity is highlighted by the prevention of murine graft versus host disease by a short exposure of the donor bone marrow cells to the dipeptide ester L-Leu-L-Leu-OMe (Charley et al., 1986; Thiele et al., 1987).
KeywordsInfected Macrophage Amino Acid Ester Amino Acid Amide Leishmanicidal Activity Amino Acid Accumulation
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