Novel agmatine analogue, γ-guanidinooxypropylamine (GAPA) efficiently inhibits proliferation of Leishmania donovani
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- 作者：Sushma Singh ; Anupam Jhingran ; Ankur Sharma ; Alina R. Simonian ; Pasi Soininen ; Jouko Vepsalainen ; Alex R. Khomutov ; Rentala Madhubala
- 关键词：γ ; -Guanidinooxypropylamine (GAPA) ; Agmatine analogue ; Leishmania donovani ; ODC-overexpressors ; Ornithine decarboxylase ; Polyamines ; Putrescine transport
- 刊名：Biochemical and Biophysical Research Communications
- 出版年：2008
- 出版时间：10 October 2008
- 年：2008
- 卷：375
- 期：1
- 页码：168-172
- 全文大小：449 K
文摘
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 Ki value of 60 μM. The ODC-overexpressors showed significant resistance to GAPA. GAPA has pKa 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.