An orally effective dihydropyrimidone (DHPM) analogue induces apoptosis-like cell death in clinical isolates of Leishmania donovani overexpressing pteridine reductase 1
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
An orally effective dihydropyrimidone (DHPM) analogue induces
apoptosis-like cell death in clinical isolates of Leishmania
donovani overexpressing pteridine reductase 1
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| Creator |
Singh, Neeloo
Kaur, Jaspreet Kumar, Pranav Gupta, Swati Singh, Nasib Ghosal, Angana Dutta, Avijit Kumar, Ashutosh Tripathi, RamaPati Siddiqi, Mohammad Imran Mandal, Chitra Dube, Anuradha |
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| Subject |
Infectious Diseases and Immunology
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| Description |
The protozoan parasite Leishmania donovani is
the causative agent of visceral leishmaniasis. The enzyme
pteridine reductase 1 (PTR1) of L. donovani acts as a
metabolic bypass for drugs targeting dihydrofolate reductase
(DHFR); therefore, for successful antifolate chemotherapy
to be developed against Leishmania, it must target
both enzyme activities. Leishmania cells overexpressing
PTR1 tagged at the N-terminal with green fluorescent
protein were established to screen for proprietary dihydropyrimidone
(DHPM) derivatives of DHFR specificity
synthesised in our laboratory. A cell-permeable molecule
with impressive antileishmanial in vitro and in vivo oral
activity was identified. Structure activity relationship based on homology model drawn on our recombinant enzyme
established the highly selective inhibition of the enzyme by
this analogue. It was seen that the leishmanicidal effect of
this analogue is triggered by programmed cell death
mediated by the loss of plasma membrane integrity as
detected by binding of annexin V and propidium iodide
(PI), loss of mitochondrial membrane potential culminating
in cell cycle arrest at the sub-G0/G1 phase and oligonucleosomal
DNA fragmentation. Hence, this DHPM
analogue [(4-fluoro-phenyl)-6-methyl-2-thioxo-1, 2, 3, 4-
tetrahydropyrimidine-5-carboxylic acid ethyl ester] is a
potent antileishmanial agent that merits further pharmacological
investigation.
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| Publisher |
Springer Verlag
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| Date |
2009
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/251/1/PARASITOLOGY_RESEARCH%2C105(5)%2C1317%2D1325%2C2009[21].pdf
Singh, Neeloo and Kaur, Jaspreet and Kumar, Pranav and Gupta, Swati and Singh, Nasib and Ghosal, Angana and Dutta, Avijit and Kumar, Ashutosh and Tripathi, RamaPati and Siddiqi, Mohammad Imran and Mandal, Chitra and Dube, Anuradha (2009) An orally effective dihydropyrimidone (DHPM) analogue induces apoptosis-like cell death in clinical isolates of Leishmania donovani overexpressing pteridine reductase 1. Parasitology Research, 105 (5). pp. 1317-1325. |
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| Relation |
http://dx.doi.org/10.1007/s00436-009-1557-z
http://www.eprints.iicb.res.in/251/ |
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