Targeting the polyamine biosynthetic enzymes: a promising approach to therapy of African sleeping sickness, Chagas’ disease, and leishmaniasis

Abstract

Trypanosomatids depend on spermidine for growth and survival. Consequently, enzymes involved in spermidine synthesis and utilization, i.e. arginase, ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (AdoMetDC), spermidine synthase, trypanothione synthetase (TryS), and trypanothione reductase (TryR), are promising targets for drug development. The ODC inhibitor alpha-difluoromethylornithine (DFMO) is about to become a first-line drug against human late-stage gambiense sleeping sickness. Another ODC inhibitor, 3-aminooxy-1-aminopropane (APA), is considerably more effective than DFMO against Leishmania promastigotes and amastigotes multiplying in macrophages. AdoMetDC inhibitors can cure animals infected with isolates from patients with rhodesiense sleeping sickness and leishmaniasis, but have not been tested on humans. The antiparasitic effects of inhibitors of polyamine and trypanothione formation, reviewed here, emphasize the relevance of these enzymes as drug targets. By taking advantage of the differences in enzyme structure between parasite and host, it should be possible to design new drugs that can selectively kill the parasites.

Binding and inhibition of human spermidine synthase by decarboxylated S‐adenosylhomocysteine

“…[1][2][3][4][5][6][7] Spermidine is a major polyamine that serves multiple functions in growth including its role as a precursor of hypusine, which is essential for the activity of the eukaryotic initiation factor elF-5A. [8][9][10][11] Polyamines are formed in eukaryotes and in many, but not all, prokaryotes by the action of aminopropyltransferases.…”

Insights into the redox biology of Trypanosoma cruzi: Trypanothione metabolism and oxidant detoxification

“…T. (reviewed in [54,55]). Spermidine has been identified as the crucial 268 polyamine for parasite proliferation [56,57] and accordingly, the 269 enzymes involved in its synthesis or that of its precursors have been…”

“…shown to be essential (reviewed in [54]). In T. cruzi the scenario is 271 rather different and polyamine metabolism has been a matter of 272 controversy for almost 20 years [55].…”

Endocellular polyamine availability modulates epithelial-to-mesenchymal transition and unfolded protein response in MDCK cells

“…Spots were subsequently identified with LC-Mass spectrometry (see Table 1), a-enolase (spots 4, 5, 6), vimentin (spots 7, 8, 9), glucose-regulated protein 78 kDa (GRP78, spots 10, 11, 12), glucose-regulated protein 94 kDa (GRP94, spot 13), or HSP90 a/b (spots 16,17,18). Each gel was performed in triplicate and analyzed using PDQuest Advanced software (Bio-Rad).…”

“…The availability of specific inhibitors of ODC and SAMDC has allowed to establish the essential role of polyamines in many processes, including cell growth, [6][7][8][9] differentiation, 10,11 cell adhesion, 12 induction of apoptosis, 13 and signal transduction. [14][15][16] On this basis, DFMO administration has been suggested for the treatment of infectious diseases, 17 protozoal parasitism 18 or, with modest results, cancer 19 and hyper proliferative diseases. 20 Polyamines may act as ligands of DNA, RNA, phospholipids, nucleotide triphosphates, or proteins and act as effectors of gene expression and signal transduction.…”