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

Dina le Roux; Pieter B Burger; Jandeli Niemand; Anne Grobler; Patricia Urbán; Xavier Fernàndez-Busquets; Robert H Barker; Adelfa E Serrano; Abraham I Louw; Lyn-Marie Birkholtz

doi:10.1016/j.ijpddr.2013.11.003

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

Int J Parasitol Drugs Drug Resist. 2013 Dec 5;4(1):28-36. doi: 10.1016/j.ijpddr.2013.11.003. eCollection 2014 Apr.

Affiliations

¹ Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria, Private Bag X20, Hatfield 0028, South Africa.
² DST/NWU Preclinical Drug Development Platform, North-West University, Potchefstroom 2531, South Africa.
³ Nanobioengineering Group, Institute for Bioengineering of Catalonia, Baldiri Reixac 10-12, Barcelona E08028, Spain ; Barcelona Centre for International Health Research (CRESIB), Hospital Clínic-Universitat de Barcelona, Rosselló 149-153, Barcelona E08036, Spain ; Biomolecular Interactions Team, Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, Barcelona E08028, Spain.
⁴ Genzyme Corporation, 153 Second Avenue, Waltham, MA 02451, USA.
⁵ University of Puerto Rico-School of Medicine, Department of Microbiology and Medical Zoology, P.O. Box 365067, San Juan PR 00936-5067, Puerto Rico.

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, 5'-{[(Z)-4-amino-2-butenyl]methylamino}-5'-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-5'-{[(Z)-4-aminobut-2-enyl]methylamino}-5'-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.

Keywords: AdoMet, S-adenosyl-l-methionine; AdoMetDC, S-adenosyl-l-methionine decarboxylase; DFMO, dl-α-difluoromethylornithine; Genz-644043, 2′-fluoro-5′-{[(Z)-4-amino-2-butenyl]methylamino}-5′-deoxyadenosine; Genz-644053, 2-chloro-5′-{[(Z)-4-amino-2-butenyl]methylamino}-5′-deoxyadenosine; Genz-644131, 8-methyl-5′-{[(Z)-4-aminobut-2-enyl]methylamino}-5′-deoxyadenosine; Immunoliposomes; MDL73811, 5′-{[(Z)-4-amino-2-butenyl]methylamino}-5′-deoxyadenosine; ODC, ornithine decarboxylase; Plasmodium; Polyamines; S-adenosyl-l-methionine decarboxylase; dcAdoMet, decarboxylated S-adenosyl-l-methionine.