This document summarizes the history and development of semi-synthetic artemisinin as an antimalarial drug. It discusses how artemisinin was originally extracted from sweet wormwood but is now partially produced synthetically through fermentation and chemical conversion. This has made the drug more stable in supply and lower in price, improving access for developing countries. The development involved researchers at UC Berkeley, Amyris, Sanofi, and was funded through partnerships including the Bill & Melinda Gates Foundation. The semi-synthetic production method is expected to provide a steady supply of artemisinin to treat millions annually.

1. Semi-synthetic Artemisinin
Dr. Mansij Biswas
Dept. of Clinical Pharmacology
KEM Hospital

2. History
2nd century BC Traditional Chinese
Medicine Doctors
Empirical usage
of sweet wormwood
(Artemisia annua) for fever
23/05/1967 Chinese government (Mao
Tse-toung)
Launch of the 523 malaria
research programme
1971 AMMS (academy of
military medical science);
Shanghai Institute of
Materia medica
Isolation of artemisinin
(quinghaosu) from sweet
wormwood
1980 Welcome Trust Information to the world
2006 WHO ACT recommended as gold
standard treatment
worldwide11/08/14 2

3. MECHANISM OF ACTION
• Unique structure bearing
endoperoxide lactone (1,2,4 –
trioxane)
• High selectivity due to its
interaction with haem which
accumulates in parasitized
RBC’s as byproduct of
haemoglobin lysis
• This endoperoxide lactone
moiety form a complex with
Fe(II) of haem & generate highly
reactive free radicals which
causes lysis of the parasite
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4. Source:
It is the active principle of the plant Artemisia annua used in
chinese traditional medicine as quinghaosu
Derivatives marketed in India:
• Artemether (oil soluble)
• Artesunate (water soluble)
• Arteether (developed in India)
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5. Problem
Price and Availability
• Difficulty in distribution in remote areas, which are
most affected with malaria
• Volatile crop- grows commercially in just a small
slice of the world and fluctuates drastically in supply
and price
• Yield and quality vary depending on weather, region,
growing practices, and market conditions
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6. • Concentration of the active ingredient in
wormwood is low- vast acres of land are needed to
produce sufficient quantities of the Active
Pharmaceutical Ingredient (API)
• Only China & Vietnam provide enough fields to grow
plant in large scale
• Experimental cultivation- Kenya, Tanzania,
Madagascar
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7. Breakthrough
• 2001 – University of California, Berkeley, professor of
chemical engineering Jay Keasling- implanted a
combination of wormwood and yeast (Saccharomyces
cerevisiae) genes into bacteria produceing a chemical that
could be chemically converted to artemisinin
• Further research turned up another gene in 2006 that,
when inserted into yeast with the earlier genes,
synthesize small amounts of artemisinic acid
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8. • Using synthetic biology techniques from Keasling’s
lab, Amyris added that gene to yeast along with
other plant genes to boost artemisinic acid
production by a factor of 15
• Sanofi developed its own proprietary photochemical
process to convert artemisinic acid to artemisinin
• On April 11, 2013, Sanofi launched the large-scale
production of this partially synthetic version of
artemisinin
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10. 11/08/14 10

11. • Production of artemisinic acid through fermentation-
performed by Huvepharma, Bulgaria
• Synthetic transformation of the artemisinic acid into
artemisinin via photochemistry- performed at
Sanofi’s Garessio site at Italy
• Sanofi planned to produce 35 tons of artemisinin in
2013 and, on average, 50 to 60 tons a year on & from
2014, which corresponds to between 80 and 150
million ACT treatments
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12. Advantage
• low price for developing countries (UCB- royalty-free
licensing of the process, Sanofi’s no-profit, no-loss
production model
• Though the price of ACTs will vary from product to
product, the new source for its key ingredient, in
addition to the plant- derived supply, should lead to
a stable cost and steady supply of artemisinin
• ultimately ensuring greater availability of treatment
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13. The Partnership
• Keasling's UC Berkeley research lab- initial discovery
• Amyris, biotechnology firm in California- refined the
process to enable industrialization
• Sanofi- large scale production and marketing
• OneWorld Health, the drug development program for
PATH, an international nonprofit organization aiming to
transform global health through innovation
• Two grants totaling $53.3 million from the Bill & Melinda
Gates Foundation
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16. • Faiz MA, Rahman E, Hossain MA, Rahman MR, Yunus EB, Samad R, Hossain MA; “A
randomized controlled trial comparing artemether and quinine in the treatment of
cerebral malaria in Bangladesh”; Indian J Malariol. 2001 Mar-Jun;38(1-2):9-18
• Mohanty AK, Rath BK, Mohanty R, Samal AK, Mishra K; “Randomized control trial of
quinine and artesunate in complicated malaria”; Indian J Pediatr. 2004 Apr;71(4):291-5
• Dondorp A, Nosten F, Stepniewska K, Day N, White N; “Artesunate versus quinine for
treatment of severe falciparum malaria: a randomised trial”; The Lancet; 2005,
366(9487):717-725
• Tran Tinh Hien, M.D., Nicholas P.J. Day, B.M., B.ch., Nguyen Hoan Phu, M.D., Nguyen Thi
Hoang Mai, M.D., Tran Thi Hong Chau, M.D., Pham Phu Loc, M.D. et al; “A Controlled
Trial of Artemether or Quinine in Vietnamese Adults with Severe Falciparum Malaria”; N
Engl J Med 1996; 335:76-83
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