Assessment of Plasmodium Falciparum RNA Pseudouridylate Synthase (Putative) as Novel Drug Target
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Malaria is a major public health problem
associated with high mortality, morbidity rates and undue
economic burden in sub-Saharan countries. Presently,
every year, 300 to 500 million people suffer clinically from
malaria and 90% of them in sub-Saharan Africa. About
1.5 to 3 million people die of malaria every year and 85%
of these occur in Africa. One child dies of malaria
somewhere in Africa every 20 second, and there is one
malarial death every 12 sec somewhere in the world. This
is also a damaging economic burden for these sub-Saharan
Africa countries as huge work force time and resources are
expended for treatment. Plasmodium falciparum (hence
forth Pf) is the most severe of all the human malaria
parasites. This organism is continuing to develop
resistance to all known drugs and therapeutic regime. One
of the mechanisms of resistance in Pf is the modification of
the drug target. Hence, it is expedient to continuously
discover novel drug targets in Pf and to discover or
develop new drugs against such targets. Drug-able
signaling pathways have been shown to have inherent
mechanism capable of deterring drug resistance. Using
computational techniques, we have identified some
proteins in the signaling pathways of Pf as putative targets
for anti-plasmodia drug. RNA pseudouridylate synthase,
which also plays a key role in RNA synthesis and
ribosomal function, is one of such proteins. Initial virtual screening of this enzyme against drug and chemical
databases has been performed to identify compounds that
can inhibit this enzyme. This led us to compounds which
inhibit nucleotide metabolism. This is a work in progress
whose current state is hoped for presentation at this
conference. In order to determine the identified
compounds IC50, the identified compounds will be
screened in vitro against the enzyme. We have currently
completed the establishment of the enzyme functionally
expression in E. coli and purification. Thereafter, the
drugs will be screened for their anti-plasmodia activity
using cultured Pf and the IC50 for each drug will be
determined. In order to assess their safety, the selectivity
index of compounds that showed in vitro anti-plasmodia
activity will be determined using human cultured cell lines.
The last stage of this study will involve screening the
compounds in an in vivo mouse model of malaria. It is
hoped that the result of this study will prove this enzyme
as a novel target for antimalarial drug. And provide as
input, critical drug targets in to our established Structure
Based Drug Design (SBDD) pipeline
Keywords
QA75 Electronic computers. Computer science, QH301 Biology