(NAS Colloquium) Proteolytic Processing and Physiological Regulation (1999) / Chapter Skim
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Cysteine protease inhibitors as chemotherapy: Lessons from a parasite target
Cysteine protease inhibitors as chemotherapy: Lessons from a parasite target
Pages 11015-11022
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From page 11015... ...
We now report that specific cysteine protease inhibitors kill Leishmania parasites in vitro, at concentrations that do not overtly affect mammalian host cells. Inhibition of Leishmania cysteine protease activity was accompanied by defects in the parasite's Iysosome/endosome compartment resembling those seen in Iysosomal storage diseases.
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From page 11016... ...
For ImmunoGold labeling, a polyclonal antiserum raised against the native L major cpB was used in a 1:20 or 1:100 dilution, followed by a secondary antibody conjugated with 10-nm gold particles (goat antibody to rabbit IgG, 1:50, Amersham Life Sciences)
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From page 11017... ...
Even after 10 days no parasites could be detected, indicating a complete cure of the Leishmania culture by the cysteine protease inhibitors. To confirm that the inhibitors could access the intracellular cysteine proteases of L
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From page 11018... ...
The hydrazide inhibitors and the pseudopeptide inhibitor produced very similar effects on the organelle structure within the parasites. After 24 h of treatment, myelin figures, undigested cell debris, dense bodies, and multivesicular bodies Compound (40 ,uM)
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From page 11019... ...
suggesting that they may be secretory vesicles. Because of the selective arrest of parasite versus host cell growth by inhibitors added to cultures, the efficacy of the cysteine protease inhibitors in vivo was evaluated in Leishmania-infected BALB/c mice.
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From page 11020... ...
would need to be eliminated to completely prevent parasite invasion or replication in host cells and lesion development in vivo. The inhibition of both amastigote infection of macrophages and lesion development in mice by cysteine protease inhibitors reported here is comparable to, and consistent with, the results of double cysteine protease gene knockout studies in L
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From page 11021... ...
. The selectivity of the inhibitor effects on the parasite suggests that cysteine proteases are crucial to the parasite, whereas host cells are less sensitive to cysteine protease inhibitors at the concentrations used.
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From page 11022... ...
11022 Colloquium Paper: Selzer et al.
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