Targeting polyamine metabolism for finding new drugs against leishmaniasis: a review.

Abstract

Leishmaniasis is a neglected disease affecting more than 12 million people worldwide. The most used drugs are pentavalent antimonials that are very toxic and display the problem of drug resistance, especially in endemic regions such as Bihar in India. For this reason, it is urgent to find new and less toxic drugs against leishmaniasis. To this end, the understanding of pathways affecting parasite survival is of prime importance for targeted drug discovery. The parasite survival inside the macrophage is strongly dependent on polyamine metabolism. Polyamines are, in fact, very important for cell growth and proliferation. In particular, spermidine (Spd), the final product of the polyamine biosynthesis pathway, serves as a precursor for trypanothione (N1,N8- bis(glutathionyl)spermidine, T(SH)2) and hypusine (N(ε)-(4-amino-2-hydroxybutyl)lysine). T(SH)2 is a key molecule for parasite defense against the hydrogen peroxide produced by macrophages during the infection. Hypusination is a posttranslational modification occurring exclusively in the eukaryotic initiation factor 5A (eIF5A), which has an important role in avoiding the ribosome stalling during the biosynthesis of protein containing polyprolines sequences. The enzymes, belonging to the spermidine metabolism, i.e. arginase (ARG), ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (AdoMetDC), spermidine synthase (SpdS), trypanothione synthetase (TryS or TSA), trypanothione reductase (TryR or TR), tryparedoxin peroxidase (TXNPx), deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) are promising targets for the development of new drugs against leishmaniasis. This minireview furnishes a picture of the structural, functional and inhibition studies on polyamine metabolism enzymes that could guide the discovery of new drugs against leishmaniasis.

• Authors: Andrea Ilari, Annarita Fiorillo, Paola Baiocco, Elena Poser, Gabriella Angiulli, Gianni Colotti
• Journal: Mini reviews in medicinal chemistry (Mini Rev Med Chem) Vol. 15 Issue 3 Pg. 243-52 ( 2015) ISSN: 1875-5607 [Electronic] Netherlands
• PMID: 25769972 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antiprotozoal Agents
• Polyamines
• Protozoan Proteins
• Spermidine Synthase
• Arginase
• Carboxy-Lyases

Topics

• Antiprotozoal Agents (chemistry, pharmacology, therapeutic use)
• Arginase (antagonists & inhibitors, metabolism)
• Carboxy-Lyases (antagonists & inhibitors, metabolism)
• Catalytic Domain
• Humans
• Leishmania (drug effects)
• Leishmaniasis (drug therapy, pathology)
• Molecular Docking Simulation
• Polyamines (chemistry, metabolism)
• Protozoan Proteins (antagonists & inhibitors, metabolism)
• Spermidine Synthase (antagonists & inhibitors, metabolism)