Apicoplast is an organelle which is present in the apicomplexan parasites like Plasmodium species. Nowadys different drugs are developed which target different pathways present in the apicoplast.

1. Apicoplast: an excellent target for
antimalarial drug development

2. CONTENTS
• INTRODUCTION
• WHAT IS MALARIA?
• MALARIA DISEASE BURDEN
• TYPES OF MALARIA
• LIFE CYCLE OF MALARIA
• MALARIA CONTROL STRATEGIES
• OBJECTIVES AND USE OF ANTIMALARIAL DRUGS
• CLASSIFICATION OF ANTI MALARIAL DRUG
• WHY COMBINATION THERAPY?
• AN EXCELLENT TARGET FOR ANTIMALARIAL DRUG DEVELOPMENT(APICOPLAST)
• RESEARCH PIPELINE DRUG
• FUTURE PROSPECTS
• CONCLUSION
• REFERENCES

3. INTRODUCTION
• Malaria is a protozoal disease
• According to global malaria estimates in the year 2017, nearly 216 million people were at the risk, and
445,000 deaths occurred.
• Malaria parasite strains resistant to practically all the antimalarial drugs
• Recent advances in molecular techniques may provide a novel targets in metabolic pathways like
isoprenoid biosynthesis, fatty acid biosynthesis and heme biosynthesis in the apicoplast of Plasmodium
• Combination therapy has proved to be a success in the combination of sulphadoxine and pyrimethamine,
which targets two different steps in the folate pathway of malaria parasite.
• various drug targets so far discovered in apicoplast-related anabolic pathways, especially, with a sharper
focus on the possibility to target more than one enzyme at a time in a particular metabolic pathway

4. Malaria
• Malaria is an acute infectious disease
• Causative agent : Plasmodium species
• 4 species infecting humans
i. P. falciparum
ii. P. vivax
iii. P. malariae
iv. P. ovale
• Transmitted by female Anopheles mosquito
• Characterized by high fever with rigor,
anemia, profuse sweating Snow, R. W., Guerra, C. A., Noor, A. M., Myint, H. Y., and Hay, S. I. 2005.

5. Malaria Disease Burden
One third of world population at risk
~200 million infections annually
0.6 million deaths (90% in Africa)
3,000 children under 5 die every day
$12 billion lost GDP
Consumes 40 % of public health spending
Skinner-Adams, T. S., McCarthy, J. S., Gardiner, D. L., and Andrews, K. T. 2008.

6. Plasmodium falciparum Plasmodium vivax Plasmodium malariae Plasmodium ovale
Most dangerous species
causes an acute, rapidly
fulminating disease i.e.
characterized by
persistent high fever,
orthostatic hypotension,
and massive
erythrocytosis capillary
obstruction and death if
treatment is delayed
Causes a milder form of
the disease
Common to many tropical
regions
Rarely encountered
Types of Plasmodium species
Table 1: Types of Plasmodium species

7. Life cycle of Malaria Parasite
Fig 1 : Life cycle of Plasmodium sp. www.cdc.gov

8. Vector control methods:
Barrier
Insecticides
Biological
Environmental
Drugs
Vaccines
DrugsDrugs & Vaccines
Infected erythrocytesInsecticide treated bed nets
Malaria Control Strategies
Fig2 : Malaria Control Strategies

9. OBJECTIVES AND USE OF ANTIMALARIAL DRUGS
• To prevent clinical attack of malaria(Prophylactic)
• To treat clinical attack of malaria(clinical curative)
• To completely eradicate the parasite from the patients body(radical
curative)
• To cutdown human to mosquito transmission( gametocidal)

10. Nature of the treatment Drug name Mechanism of action
Causal prophylaxis Primaquine Prevent maturation or
destroy sporozoites and thus
prevent erythrocytic
invasion
Suppressive prophylaxis Quinine, Chloroquinine Inhibit erythrocytic phase
and rupture of the infected
erythrocytes.
Clinical cure Mefloquine Prevents polymerization of
Hb
Radical cure Proguanil Inhibit dihydrofolate
reductase
Gametocidal Artemisinin Decrease protein synthesis
and lysis of cell
Classification of Antimalarial drugs
Table 2: Classification of Antimalarial drug

11. • Rapid clinical and parasitological cure
• High cure rates and low recrudescence rate
• Absence of parasite resistance( the components prevent
development of resistant to each other)
• Good tolerability profile
Why combination therapy?

12. An excellent target for antimalarial
drug development
Fig3 : An excellent target for antimalarial drug development
Shears, M. J., MacRae, J. I., Mollard, V., Goodman, C. D., Sturm, A., Orchard, L. M., ... & McFadden, G. I.
(2017).

13. Possible Targets for Combination Therapy of Malaria
Fig 4: Fatty acid biosynthesis pathway

14. Compound Structure Mechanism of action
Hexachlorophene Hexachlorophene a known inhibitor of Fab
G accounted to inhibit liver stage growth
in vitro.
Thiolactomycin Inhibit the rate-limiting enzyme
of the pathway ACCases
Ceruline
Inhibit KAS III (
β-ketoacyl-ACP
synthase III)
Clodinafop Inhibit carboxyltransferase domain of the
apicoplastic form of ACCase,
Fatty acid biosynthesis inhibitors
Table 3: Fatty acid biosynthesis inhibitor

15. Heme biosynthesis pathway
Fig 5: Heme biosynthesis pathway

16. Compound name Structure Function
Oxyfluorfen Diphenylether-type herbicides are
extremely potent inhibitor of
protoporphyrinogenoxidase, a
membrane-bound enzyme involved in the
heme and chlorophyll biosynthesis
pathways.
Succinyl acetone Inhibit both parasite ALAD.
Atovaqunone Synthetic with antiprotozoal activity.
Atovoquone blocks the mitochondrial
electron transport at complex III of the
respiratory chain of protozoa, thereby
inhibiting pyrimidine synthesis,
preventing DNA synthesis and leading to
protozoal death.
Aclonifen Blocks the mitochondrial electron
transport at complex III of the
respiratory chain of protozoa,
Heme Biosynthesis inhibitors
Table 4: Heme biosynthesis inhibitors

17. Isoprenoid Biosynthesis pathway
Fig 6: Isoprenoid biosynthesis pathway

18. Compound name Structure Function
Fosmidomycin Fosmidomycin is an antibiotic that
was originally isolated from culture
broths of bacteria of the genus
Streptomyces. It specifically inhibits
DXP reductoisomerase, a key
enzyme in the non-mevalonate
pathway of isoprenoid biosynthesis.
Bisphosphonates
Inhibits the activity of farnesyl
pyrophosphate synthetase, an
enzyme involved in terpenoids
biosynthesis. Inhibition of this
enzyme prevents the biosynthesis of
isoprenoid.
Isoprenoid Biosynthesis inhibitors
Table5 : Isoprenoid Biosynthesis inhibitors

19. COMPOUND NAME MARKETED NAME PHASES OF CLINICAL
TRIAL
Fosmidomycin Phase1-3 completed for
plasmodium infection
Hexachlorophene pHisoHex Completed clinical trials
Ceruline Ceruletide Completed clinical trials
Atovaquone Mepron Completed clinical trials
Research pipeline drugs
Table 6 : Research pipeline drugs

20. Future Prospects
• More than a few known and new lead compounds have been
screened for their inhibitory activity against metabolic enzymes like
DXR, DXS and FPPS in isoprenoid pathway; ENR, the KAS family,
KAR and HAD in FAS II; and ALAD and PPO in heme synthesis
pathways.
• We do hope that there remains much to be done in the pursuit of
new combinations of drugs which target different enzymes
belonging to one particular metabolic pathway.

21. Conclusion
• Apicoplast is indispensable for growth and survival of the malaria parasite and has been
extensively targeted .
• The apicoplast houses important biosynthetic pathways as well as prokaryotic like
housekeeping processes offering attractive avenues for drug development.
• The discovery of the susceptibility of the apicoplast to antimicrobial antibiotics has driven
extensive investigation into the discovery of novel apicoplast targeting compounds.
• The apicoplast metabolic processes especially the prokaryote like fatty acid biosynthetic
pathway has been extensively targeted over the recent years using medicinal chemistry and
SAR based approaches

22. REFERENCES
• McFadden, G. I., & Yeh, E. (2017). The apicoplast: now you see it, now yoLow, L. M.,
Stanisic, D. I., & Good, M. F. (2017).
• Exploiting the apicoplast: apicoplast-targeting drugs and malaria vaccine development.
Microbes and infection.u don’t. International journal for parasitology, 47(2-3), 137-144.
• Shears, M. J., Botté, C. Y., & McFadden, G. I. (2015). Fatty acid metabolism in the
Plasmodium apicoplast: Drugs, doubts and knockouts. Molecular and biochemical
parasitology, 199(1-2), 34-50. Chakraborty, A. (2016). Understanding the biology of the
Plasmodium falciparum apicoplast; an excellent target for antimalarial drug
development. Life sciences, 158, 104-110.

23. Cont.…..
• Duvalsaint, M., & Kyle, D. E. (2018). Phytohormones, isoprenoids and role of the
apicoplast in recovery from dihydroartemisinin-induced dormancy of Plasmodium
falciparum. Antimicrobial agents and chemotherapy, AAC-01771.
• Rathnapala, U. L., Goodman, C. D., & McFadden, G. I. (2017). A novel genetic
technique in Plasmodium berghei allows liver stage analysis of genes required for
mosquito stage development and demonstrates that de novo heme synthesis is
essential for liver stage development in the malaria parasite. PLoS pathogens,
13(6), e1006396.