4.4 Article

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

Publisher

ELSEVIER SCI LTD
DOI: 10.1016/j.ijpddr.2013.11.003

Keywords

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

Funding

  1. Department of Science and Technology through the South African Malaria Initiative
  2. University of Pretoria
  3. South African National Research Foundation
  4. Ministerio de Economia y Competitividad, Spain [BIO2011-25039]
  5. FEDER funds
  6. Generalitat de Catalunya, Spain [2009SGR-760]

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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. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

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