title: Novel agmatine analogue, gamma-guanidinooxypropylamine (GAPA) efficiently inhibits proliferation of Leishmania donovani by depletion of intracellular polyamine levels.
abstract: 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.
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi 110067, India.
authors.forename: Sushma
authors.initials: S
authors.lastname: Singh
authors.forename: Anupam
authors.initials: A
authors.lastname: Jhingran
authors.forename: Ankur
authors.initials: A
authors.lastname: Sharma
authors.forename: Alina R
authors.initials: AR
authors.lastname: Simonian
authors.forename: Pasi
authors.initials: P
authors.lastname: Soininen
authors.forename: Jouko
authors.initials: J
authors.lastname: Vepsalainen
authors.forename: Alex R
authors.initials: AR
authors.lastname: Khomutov
authors.forename: Rentala
authors.initials: R
authors.lastname: Madhubala
mesh_terms: 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*
chemical_list: D000981:Antiprotozoal Agents; D015317:Biogenic Polyamines; D006146:Guanidines; D011437:Propylamines; D000376:Agmatine; C045522:guanidinooxypropylamine