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

Journal Article · Fri Oct 10 00:00:00 EDT 2008 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/j.bbrc.2008.07.143· OSTI ID:21143897

Singh, Sushma; Jhingran, Anupam; Sharma, Ankur ^[1]; Simonian, Alina R ^[2]; Soininen, Pasi; Vepsalainen, Jouko ^[3]; Khomutov, Alex R ^[2]; Madhubala, Rentala ^[1]

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1. School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi 110067 (India)
2. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991 (Russian Federation)
3. Department of Chemistry, University of Kuopio, P.O. Box 1627, FI-70211 Kuopio (Finland)

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{sub i} value of {approx}60 {mu}M. The ODC-overexpressors showed significant resistance to GAPA. GAPA has pK{sub 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.

• OSTI ID: 21143897
• Journal Information: Biochemical and Biophysical Research Communications, Vol. 375, Issue 1; Other Information: DOI: 10.1016/j.bbrc.2008.07.143; PII: S0006-291X(08)01500-3; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CELL PROLIFERATION
DECARBOXYLASES
LEAD COMPOUNDS
ORNITHINE
PARASITES
PH VALUE
PUTRESCINE
SPERMIDINE