Novel S-adenosyl-L-methionine decarboxylase inhibitors as potent antiproliferative agents against intraerythrocytic Plasmodium falciparum parasites

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Authors

Le Roux, Dina
Burger, Pieter Buys
Niemand, Jandeli
Grobler, Anne
Urbán, Patricia
Fernàndez-Busquets, Xavier
Barker, Robert H.
Serrano, Adelfa
Louw, Abraham Izak
Birkholtz, Lyn-Marie

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Publisher

Elsevier

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.

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Keywords

Plasmodium, Polyamines, S-adenosyl-L-methionine decarboxylase, Immunoliposomes

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Citation

Le Roux, D, Burger, PB, Niemand, J, Grobler, A, Urbán, P, Fernàndez-Busquets, X, Barker, RH, Serrano, AE, Louw, AI & Birkholtz, L.-M 2014,'Novel S-adenosyl-L-methionine decarboxylase inhibitors as potent antiproliferative agents against intraerythrocytic Plasmodium falciparum parasites', International Journal for Parasitology : Drugs and Drug Resistance, vol. 4, no. 1, pp. 28-36.