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Amino Acids

, Volume 33, Issue 2, pp 359–366 | Cite as

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

  • O. Heby
  • L. Persson
  • M. Rentala
Review Article

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.

Keywords: African sleeping sickness – Chagas’ disease – Leishmaniasis – Polyamines 

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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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • O. Heby
    • 1
  • L. Persson
    • 2
  • M. Rentala
    • 3
  1. 1.Department of Molecular BiologyUmeå UniversityUmeåSweden
  2. 2.Department of Experimental Medical Science, BMCLund UniversityLundSweden
  3. 3.School of Life SciencesJawaharlal Nehru UniversityNew DelhiIndia

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