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

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Summary.

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 α-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.

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Abbreviations

AbeAdo:

5′-{[(Z)-4-amino-2-butenyl]methylamino}-5′-deoxyadenosine (MDL 73811)

AdoDATO:

S-adenosyl-1,8-diamino-3-thiooctane

AdoMet:

S-adenosylmethionine

AdoMetDC:

S-adenosylmethionine decarboxylase

APA:

3-aminooxy-1-aminopropane

CGP 40215A:

(bis{[3-(aminoiminomethyl)phenyl]methylene}carbonimidic dihydrazide trihydrochloride)

CNS:

central nervous system

dcAdoMet:

decarboxylated S-adenosylmethionine

DFMO:

DL-α-difluoromethylornithine

LmPOT1:

Leishmania major polyamine transporter 1

MGBG:

methylglyoxal-bis(guanylhydrazone)

MTA:

5′-deoxy-5′-methylthioadenosine

ODC:

ornithine decarboxylase

SpdS:

spermidine synthase

SpmS:

Spermine synthase

TryR:

trypanothione reductase

TryS:

trypanothione synthetase

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Authors and Affiliations

  1. Department of Molecular Biology, Umeå University, Umeå, Sweden

    O. Heby

  2. Department of Experimental Medical Science, BMC, Lund University, Lund, Sweden

    L. Persson

  3. School of Life Sciences, Jawaharlal Nehru University, New Delhi, India

    M. Rentala

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  2. L. Persson
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  3. M. Rentala
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Heby, O., Persson, L. & Rentala, M. Targeting the polyamine biosynthetic enzymes: a promising approach to therapy of African sleeping sickness, Chagas’ disease, and leishmaniasis. Amino Acids 33, 359–366 (2007). https://doi.org/10.1007/s00726-007-0537-9

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