Antimalarial effects in mice of orally administered peptidyl cysteine protease inhibitors

The Plasmodium falciparum cysteine protease falcipain is required for the d egradation of hemoglobin by erythrocytic malaria parasites. In prior studie s, peptidyl inhibitors of falcipain blocked hemoglobin degradation and deve lopment by cultured parasites and one of these compounds, when administered parenterally, cured Plasmodium vinckei-infected mice. We now report an eva luation of orally administered peptidyl inhibitors of falcipain in a mouse malaria model. In studies with a fluoromethyl ketone, orally administered m orpholine urea-phenylalanine-homophenylalanine-fluoromethyl ketone delayed the progression of murine malaria. In studies of a new series of vinyl sulf ones, a set of related compounds demonstrated marked inhibition of falcipai n and of parasite biological activities in vitro. One of these compounds, N -methyl piperazine urea-leucine-homophenylalanine-2-naphthalene vinyl sulfo ne, cured about 40% of mice when administered orally twice-a-day for four d ays. Our results suggest that peptidyl inhibitors of falcipain have promise as antimalarial chemotherapeutic agents. (C) 1999 Elsevier Science Ltd. Al l rights reserved.