Novel agmatine analogue, gamma-guanidinooxypropylamine (GAPA) efficiently inhibits proliferation of Leishmania donovani by depletion of intracellular polyamine levels.
The efficacy of gamma-guanidinooxypropylamine (GAPA), a novel agmatine analogue against protozoan parasite, Leishmaniadonovani 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 approximately 60microM. The ODC-overexpressors showed significant resistance to GAPA. GAPA has pK(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.
Singh
Sushma
S
School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi 110067, India.
Jhingran
Anupam
A
Sharma
Ankur
A
Simonian
Alina R
AR
Soininen
Pasi
P
Vepsalainen
Jouko
J
Khomutov
Alex R
AR
Madhubala
Rentala
R
D000376:Agmatine / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D015317:Biogenic Polyamines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D007893:Leishmania donovani / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011437:Propylamines / Q000737:chemistry / Q000494:pharmacology*
D000981:Antiprotozoal Agents; D015317:Biogenic Polyamines; D006146:Guanidines; D011437:Propylamines; D000376:Agmatine; C045522:guanidinooxypropylamine