Novel agmatine analogue, γ-guanidinooxypropylamine (GAPA) efficiently inhibits proliferation of Leishmania donovani by depletion of intracellular polyamine levels

The efficacy of γ-guanidinooxypropylamine (GAPA), a novel agmatine analogue against protozoan parasite, Leishmania donovani was evaluated. Wild-type and ornithine decarboxylase-overexpressors of L. donovani were used to study the effect and mode of action of this inhibitor. GAPA inhibited the growth...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2008-10, Vol.375 (1), p.168-172
Main Authors: Singh, Sushma, Jhingran, Anupam, Sharma, Ankur, Simonian, Alina R., Soininen, Pasi, Vepsalainen, Jouko, Khomutov, Alex R., Madhubala, Rentala
Format: Article
Language:English
Subjects:
Agmatine - pharmacology
Agmatine analogue
Animals
Antiprotozoal Agents - pharmacology
Biogenic Polyamines - antagonists & inhibitors
Biogenic Polyamines - metabolism
Biological Transport - drug effects
Cell Proliferation - drug effects
Guanidines - chemistry
Guanidines - pharmacology
Leishmania donovani
Leishmania donovani - cytology
Leishmania donovani - drug effects
Leishmania donovani - metabolism
ODC-overexpressors
Ornithine decarboxylase
Polyamines
Propylamines - chemistry
Propylamines - pharmacology
Putrescine transport
γ-Guanidinooxypropylamine (GAPA)
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Summary:The efficacy of γ-guanidinooxypropylamine (GAPA), a novel agmatine analogue against protozoan parasite, Leishmania donovani was evaluated. Wild-type and ornithine decarboxylase-overexpressors of L. donovani were used to study the effect and mode of action of this inhibitor. GAPA inhibited the growth of both promastigotes and amastigotes. Ornithine decarboxylase (ODC) activity and polyamine levels were markedly lower in cells treated with GAPA and proliferation was rescued by addition of putrescine or spermidine. GAPA inhibited L. donovani recombinant ODC with K i value of ∼60 μM. The ODC-overexpressors showed significant resistance to GAPA. GAPA has p K a 6.71 and at physiological pH the analogue can mimic protonated state of putrescine and can probably use putrescine transport system. Transport of putrescine in wild-type L. donovani promastigotes was inhibited by GAPA. We for the first time report that GAPA is a potential antileishmanial lead compound and it possibly inhibits L. donovani growth by depletion of intracellular polyamine levels.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2008.07.143