Abstract:
S-adenosyl-L-methionine decarboxylase (AdoMetDC) in the polyamine biosynthesis pathway has been
identified as a suitable drug target in Plasmodium falciparum parasites, which causes the most lethal form
of malaria. Derivatives of an irreversible inhibitor of this enzyme, 50-{[(Z)-4-amino-2-butenyl]methylamino}-
50-deoxyadenosine (MDL73811), have been developed with improved pharmacokinetic profiles
and activity against related parasites, Trypanosoma brucei. Here, these derivatives were assayed for
inhibition of AdoMetDC from P. falciparum parasites and the methylated derivative, 8-methyl-50-{[(Z)-
4-aminobut-2-enyl]methylamino}-50-deoxyadenosine (Genz-644131) was shown to be the most active.
The in vitro efficacy of Genz-644131 was markedly increased by nanoencapsulation in immunoliposomes,
which specifically targeted intraerythrocytic P. falciparum parasites.
