مراد علي أبوطالب مباركي

مجال
التميز

تميز دراسي
وبحثي، وإبداع علمي

البحوث المنشورة

البحث (1):

عنوان البحث:

Generation of quinolone antimalarials
targeting the Plasmodium falciparum mitochondrial respiratory chain for the
treatment and prophylaxis of malaria

رابط الوصول:

Link

تاريخ النشر:

 May 2012

موجز عن البحث:

There is an urgent need for new
antimalarial drugs with novel mechanisms of action to deliver effective
control and eradication programs. Parasite resistance to all existing
antimalarial classes, including the artemisinins, has been reported during
their clinical use. A failure to generate new antimalarials with novel mechanisms
of action that circumvent the current resistance challenges will contribute
to a resurgence in the disease which would represent a global health
emergency. Here we present a unique generation of quinolone lead
antimalarials with a dual mechanism of action against two respiratory
enzymes, NADH:ubiquinone oxidoreductase (Plasmodium falciparum NDH2) and
cytochrome bc(1). Inhibitor specificity for the two enzymes can be controlled
subtly by manipulation of the privileged quinolone core at the 2 or 3 position.
Inhibitors display potent (nanomolar) activity against both parasite enzymes
and against multidrug-resistant P. falciparum parasites as evidenced by rapid
and selective depolarization of the parasite mitochondrial membrane
potential, leading to a disruption of pyrimidine metabolism and parasite
death. Several analogs also display activity against liver-stage parasites
(Plasmodium cynomolgi) as well as transmission-blocking properties. Lead
optimized molecules also display potent oral antimalarial activity in the
Plasmodium berghei mouse malaria model associated with favorable
pharmacokinetic features that are aligned with a single-dose treatment. The
ease and low cost of synthesis of these inhibitors fulfill the target product
profile for the generation of a potent, safe, and inexpensive drug with the
potential for eventual clinical deployment in the control and eradication of
falciparum malaria.

المؤتمرات العلمية:

المؤتمر (1):

عنوان المؤتمر:

British Society for Parasitology

تاريخ الإنعقاد:

 April 2012

بلد
ومكان الإنعقاد:

Glasgow, UK

طبيعة المشاركة:

Oral presentation

عنوان المشاركة:

Metabolic fingerprinting of Plasmodium
falciparum

الملخص:

Despite intesive research there remains major
knowledge gaps in our understanding of the metabolic network of the malaria
parasite Plasmodium falciparum. This deficiency exacerbates our
ability to identify new targets for drug discovery at a time when new targets
are urgently required.  In order to
address this problem we have adopted a chemical biology strategy whereby
biologically selective inhibitors have been used to perturb concentration and
fluxes in intermediary metabolic pathways generating “fingerprints” of
metabolites in a time-related manner. 
In this initial study, a number of mitochondrial inhibitors selective
for specific electron transport chain complexes and mitochondrial
transporters were used to assess mitochondrial function in asexually growing
parasites. Metabolite identification was conducted using a targeted LC MS/MS
metabolomics approach.  Despite the
differing modes of action of the inhibitors, the metabolic fingerprint from
these experiments was consistent with the parasite mitochondrion playing a
key role in pyrimidine biosynthesis. 
This metabolic fingerprint leading to parasite death was quite
distinct from fingerprints obtained from biologically distinct inhibitors
e.g. heme-binding antimalarials.  In
contrast to genomic and proteomics approaches, metabolomics therefore appears
to better represent the parasites’ phenotype in response to drug perturbation.
Metabolic fingerprinting will therefore have significant utility in
understanding the mode of action, efficacy and toxicity of pharmaceutical
drugs.

المؤتمر (2):

عنوان المؤتمر:

Seventh
Annual BioMalPar Conference on The Biology and Pathology of the Malaria
Parasite

تاريخ الإنعقاد:

 May 2011

بلد
ومكان الإنعقاد:

EMBL Advanced Training Centre,
Heidelberg, Germany

طبيعة المشاركة:

Poster

عنوان المشاركة:

Targeted metabolomics of mitochondria
and mitochondrial related metabolism of Plasmodium falciparum

الملخص:

Mitochondrial metabolism during the
asexual stages of Plasmodium falciparum is not very well described, but it is
thought to play a role in orotate synthesis for pyrimidine metabolism, and in
the maintenance of critical redox/energy couples required for catabolic
pathways e.g. NADH/NAD. Expression profiles indicate plasticity of
mitochondrial metabolism, particularly during the period of commitment to
sexual maturity (gametocytogenesis). 
The essential role of the mitochondrion during both asexual and sexual
stages is underlined by the ability of mitochondrion-targeting drugs such as
atovaquone and primaquine to kill both of these developmental stages (as well
as the liver stages).  In order to
describe the roles of key components of mitochondrial metabolism and the
mechanisms underpinning mitochondrion-targeting drug-induced parasite death,
we have undertaken a targeted metabolomic study.  Herein we report initial data of
mitochondrion metabolism during parasite development and in response to
mitochondrion-targeting inhibitors.

المؤتمر (3):

عنوان المؤتمر:

British Society for Parasitology

تاريخ الإنعقاد:

April 2011

بلد
ومكان الإنعقاد:

 Nottingham, UK

طبيعة المشاركة:

Presentation of a paper

عنوان المشاركة:

Targeted metabolomics of mitochondria
and mitochondrial related metabolism of Plasmodium falciparum

الملخص:

Mitochondrial metabolism during the
asexual stages of Plasmodium falciparum is not very well described, but it is
thought to play a role in orotate synthesis for pyrimidine metabolism, and in
the maintenance of critical redox/energy couples required for catabolic
pathways e.g. NADH/NAD. Expression profiles indicate plasticity of
mitochondrial metabolism, particularly during the period of commitment to
sexual maturity (gametocytogenesis). 
The essential role of the mitochondrion during both asexual and sexual
stages is underlined by the ability of mitochondrion-targeting drugs such as
atovaquone and primaquine to kill both of these developmental stages (as well
as the liver stages).  In order to
describe the roles of key components of mitochondrial metabolism and the
mechanisms underpinning mitochondrion-targeting drug-induced parasite death,
we have undertaken a targeted metabolomic study.  Herein we report initial data of
mitochondrion metabolism during parasite development and in response to
mitochondrion-targeting inhibitors.

جوائز التكريم:

الجائزة (1):

مسمى الجائزة:

Cambridge University Press and BioMed
Central Prize for Best Talk, British Society for Parasitology 50th Spring
Meeting, University of Strathclyde, Glasgow, UK

الجهة المانحة:

British
Society for parasitology

تاريخ منح  الجائزة:

April 2012

مجال التكريم:

Student Prize for best talk in the
Malaria sessions