Antimalarial effects in mice of orally administered peptidyl cysteine protease inhibitors

被引:155
作者
Olson, JE [1 ]
Lee, GK [1 ]
Semenov, A [1 ]
Rosenthal, PJ [1 ]
机构
[1] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA 94143 USA
关键词
malaria; Plasmodium; protease; proteinase; chemotherapy; cysteine protease; protease inhibitor;
D O I
10.1016/S0968-0896(99)00004-8
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The Plasmodium falciparum cysteine protease falcipain is required for the degradation of hemoglobin by erythrocytic malaria parasites. In prior studies, peptidyl inhibitors of falcipain blocked hemoglobin degradation and development by cultured parasites and one of these compounds, when administered parenterally, cured Plasmodium vinckei-infected mice. We now report an evaluation of orally administered peptidyl inhibitors of falcipain in a mouse malaria model. In studies with a fluoromethyl ketone, orally administered morpholine urea-phenylalanine-homophenylalanine-fluoromethyl ketone delayed the progression of murine malaria. In studies of a new series of vinyl sulfones, a set of related compounds demonstrated marked inhibition of falcipain and of parasite biological activities in vitro. One of these compounds, N-methyl piperazine urea-leucine-homophenylalanine-2-naphthalene vinyl sulfone, cured about 40% of mice when administered orally twice-a-day for four days. Our results suggest that peptidyl inhibitors of falcipain have promise as antimalarial chemotherapeutic agents. (C) 1999 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:633 / 638
页数:6
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