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ARTEMISININ
SOURCE: www.nobelprize.org
MALARIA
Malaria is predominantly a disease of the developing
world disease is caused by Plasmodium spp.
WHO World Malaria Report (2014): around 3.4 billion
people at risk.
TREATMENT OF MALARIA
Artemisinin plays a central role in combating the
increasingly drugresistant, malaria-causing parasite Plasmodium
falciparum.
Artemisinin-based combination therapy (ACT) is currently
the most
effective means to treat and reduce the transmission rate
DISCOVERY
1950 Failure to eradicate malaria; the disease rebounded
1967 Research programme Project 523 under leadership
of Tu Youyou
Investigated more than 2,000 Chinese herb preparations
and identified 640 hits that had possible antimalarial
activities.
380 extracts obtained from ~200 Chinese herbs were
evaluated against a mouse model of malaria.
The turning point came when an Artemisia annua leaf
extract showed inhibition against parasite growth.
4 October 1971 a nontoxic, neutral extract that was 100%
effective against parasitemia in mice infected with
INTRODUCTION
Artemisinin (historically as qinghao): SECONDARY
METABOLITE
Obtained from Artemisia annua
(sweet wormwood), an herb
employed inChinese traditional
medicine.
Belongs to Asteraceae family.
Artemisinin is stored in glandular
trichomes on the surface of the
leaves/stems and on the corolla
and receptacles of the florets.
STRUCTURE AND
PROPERTIES
1972
a sesquiterpenoid lactone with
endoperoxide ring.
colorless crystalline substance
molecular weight of 282 Da,
molecular formula of C15H22O5,
and
Structure of
artimisinin
Its
melting
point of 156157 C
major role
Antimalarial property- a new class of antimalarial agents that
rapidly kill the malaria parasites at an early stage of their
development.
Hepatitis B
A range of cancer cell lines
Image source:
MODE OF ACTION
When
DERIVATIVES OF ARTEMISININ
The therapeutic value of artemisinin was limited by its low
solubility in both oil and water, and this has lead to the
development of semi-synthetic drugs with pharmacological
properties superior to those of the parent.
The most important such derivatives are artemether, arteether
and artesunate which exhibit greater potency than artemisinin
itself, as well as improved solubility, and favourable metabolic
and hydrolytic stabilities.
BIOSYNTHETIC PATHWAY OF
ARTEMISININ
The Biosynthesis of artemisinin involves:
Phase 1 (isopentenyl pyrophosphate to amorpha4,11-diene)
Phase 2 (amorpha-4,11-diene to
dihydroartemisinic acid)
Phase 3 (dihydroartemisinic acid to artemisinin)
BIOSYNTHETIC
PATHWAY OF
ARTEMISININ
METABOLIC ENGINEERING IN
PLANTS
by overexpressing key genes from this pathway
eg CYP
by overexpression of heterologous genes in A.
annua
By down-regulating enzymatic reactions that
compete with ADS for its use, such as squalene
synthase (SQS) involved in sterol biosynthesis.
OVEREXPRESSION OF
HETEROLOGOUS GENES IN A.
ANNUA
isopentenyl transferase gene (ipt) from Agrobacterium
tumefaciens
It codes for the enzyme, isopentenyl transferase (IPT)- it catalyzes
the condensation of isopentenyl diphosphate (IPP) to form
isopentenyl AMP (iPMP)
reports have shown that overexpression of IPT increases the
content of chlorophyll and artemisinin content is higher in A. annua
plants with higher chlorophyll
the chlorophyll content increased by 2060%, and artemisinin
content increased by 3070% in the transgenic plants.
STAGE 1
Engineering of the yeast strain
by overexpression of genes of
mevalonate pathway &
expression of A. annua
amorphadiene synthase.
STAGE 2
Oxidation of amorphadiene to
artemisinic acid by expression of
CYP71AVI,
CPR1, cytb5 and dehydrogenases.
STAGE 3
Extraction of artemisinic acid
and its conversion to
artemisinin.
PLAC promoter
Adapted from
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