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Week 2: Malaria and Natural Products 1 17 JULY 2016 HSSP TRAVIS DELANO

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Week 2: Malaria and Natural Products

117 JULY 2016 HSSP TRAVIS DELANO

The Deadliest Disease in Human History

•Responsible for ½ of human deaths since the stone age

•Mosquitos are by far the deadliest animal, largely because of malaria

•(Not a neglected tropical disease)

Page 3: Week 2: Malaria and Natural Products - MIT ESP€¦ · •Chemical Synthesis •13 steps, ~5% yield •Semi-synthesis •Uses genetically engineered yeast •3 steps, ~30% yield 11

Malaria Basics

•Caused by parasites called protozoans• Plasmodium (5 types)

• P. falciparum is most deadly, P. vivax outside sub-Saharan Africa

•Transmitted by infected female mosquitos• Anopheles (30/400 species)

•Transmission is frequently worse during or after rainy season

Plasmodium in mosquito saliva

Page 4: Week 2: Malaria and Natural Products - MIT ESP€¦ · •Chemical Synthesis •13 steps, ~5% yield •Semi-synthesis •Uses genetically engineered yeast •3 steps, ~30% yield 11

Symptoms

• Initial infection occurs in the liver (8-30 days)

• Spreads to red blood cells, reproduce, burst,

repeat

• Symptoms usually begin 10-15 days after

infection

• Fever, fatigue, vomiting, headaches, seizures,

coma, deathChild with malaria, Ethiopia

Page 5: Week 2: Malaria and Natural Products - MIT ESP€¦ · •Chemical Synthesis •13 steps, ~5% yield •Semi-synthesis •Uses genetically engineered yeast •3 steps, ~30% yield 11

Range

Page 6: Week 2: Malaria and Natural Products - MIT ESP€¦ · •Chemical Synthesis •13 steps, ~5% yield •Semi-synthesis •Uses genetically engineered yeast •3 steps, ~30% yield 11

Disease Burden

• 214 Million cases in 2015

• 428,000 deaths in 2015

• 65% of cases in people younger than 15

• Good progress since 2000:

• Incidence down 37%

• Mortality rate down 60%

Page 7: Week 2: Malaria and Natural Products - MIT ESP€¦ · •Chemical Synthesis •13 steps, ~5% yield •Semi-synthesis •Uses genetically engineered yeast •3 steps, ~30% yield 11

Prevention: Vector Control

•Insecticide-treated nets are most effective• Mosquitos primarily feed at night

• Must be properly maintained and used

•Indoor spraying of insecticides• Works best when at least 80% of houses are

targeted

• Effective for 3-6 months

Bed enclosed by long-lasting insecticidal net (LLIN)

Page 8: Week 2: Malaria and Natural Products - MIT ESP€¦ · •Chemical Synthesis •13 steps, ~5% yield •Semi-synthesis •Uses genetically engineered yeast •3 steps, ~30% yield 11

Insecticide Resistance

•Resistance is developed by mosquitos, not plasmodium

•Pyrethoids are only recommended class

•Insecticide-resistance is becoming prevalent

•Some nets are now treated with two drugs

•Monitoring and new drug development are critical

Typical pyrethoid structure

Page 9: Week 2: Malaria and Natural Products - MIT ESP€¦ · •Chemical Synthesis •13 steps, ~5% yield •Semi-synthesis •Uses genetically engineered yeast •3 steps, ~30% yield 11

Malaria Treatment•Preventative drugs available• Sulfadoxine-pyrimethamine

•Best treatment is artemisinin-combination therapy• Must confirm diagnosis first

• Must not be used alone

• Resistance has developed

• More costly than others

artemisinin

Page 10: Week 2: Malaria and Natural Products - MIT ESP€¦ · •Chemical Synthesis •13 steps, ~5% yield •Semi-synthesis •Uses genetically engineered yeast •3 steps, ~30% yield 11

Artemisinin: A Natural Product•Drug can be isolated from sweet wormwood

•Has been used for malaria treatment for over 2000 years

•Discovered in 1967 by Tu Youyou• Shared Nobel prize in 2015

•Likely acts via endoperoxide

artemisinin

Page 11: Week 2: Malaria and Natural Products - MIT ESP€¦ · •Chemical Synthesis •13 steps, ~5% yield •Semi-synthesis •Uses genetically engineered yeast •3 steps, ~30% yield 11

Artemisinin Three Ways

•Biosynthesis

•Chemical Synthesis• 13 steps, ~5% yield

•Semi-synthesis• Uses genetically engineered yeast

• 3 steps, ~30% yield

Natural Products vs. Synthetics

Page 13: Week 2: Malaria and Natural Products - MIT ESP€¦ · •Chemical Synthesis •13 steps, ~5% yield •Semi-synthesis •Uses genetically engineered yeast •3 steps, ~30% yield 11

Natural Products Overview•Sources:• Bacteria, Fungi, Plants, Animals,

Marine Life

•Testing crude extracts

•Isolating the natural product

•Characterizing natural product

•Further development: isolation vs. synthesis vs. semisynthesis

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