Anti-malarial drugs

T/F the relationship of malaria-humans is much shorter than that of agriculture-humans?

False

The history of the human-malaria relationship is just as long as human-agriculture evolution

What were the dark ages of malaria?

For ~1500 years little new knowledge on the cause or treatment of malaria was forthcoming

During this time malaria spread in Europe and the new world

The disease was associated with swamps and marshes; led to the belief that malaria was caused by malignant vapors (miasmas)

Who named malaria?

Horace Walpole in 1740

Mal’aria = bad air

Who discovered the Malaria parasite?

• Charles Louis Alphonase Laveran; A French army surgeon stationed in Constantine, Alergia was the first to notice parasites in the blood of a malaria patient.

• He was awarded a nobel prize in 1907.

Which American presidents suffered from Malaria?

• George Washington

• James Monroe

• Andrew Jackson

• Abraham Lincon

• Ulysses S Grant

• James A Garfield

• Theodore Roosevelt

How many people are infected vs die of malaria annually?

• Infects between 300-500 million people annually

• 1-3 Million deaths / year

What is the cause of malaria?

Initiated by the bite of a female Anopheles mosquito which carries the sporozoite form of the parasite in its saliva and injects it into the bloodstream

there are 4 species of protozoans parasite from the genus Plasmodium

What is the lifecycle of the malaria parasite?

Sporozoite form of the parasite multiplies in the liver —> Merozoites

Merozoites invade RBC; multiply rapidly, deplete hemoglobin, red blood cells rupture and a new generation of Merozoites are released

RBC rupture occurs 48-72 hours after invasion (causes fever and chills)

Merozoites can remain dormant for years

Who first isolated the alkaloid quinine from the peruvian bark?

Two French chemists; Pelletier and Caventou

What species of Cinchona are used for Malaria treatment?

Cinchona officinalis

& C. succinruba and C. calisaya

How does quinine disrupt the malaria parasite?

Interferes with merozoite action; concentrates in parasite food vacuoles

Prevents the polymerization of heme into hemozoin resulting in toxicity to the parasite

Who developed synthetic anti-malarial drugs? what did this eventually lead to?

• The USA and Britain synthesize quinine analogues during WW1; Chloroquine, malarone and mefloquine; which target different plasmodium life cycle stages and strainsw

• But the overuse leads to resistant Plasmodium strains

= Resurgence of interest in natural quinine and the search for other anti-malarials with different MOAs

Why does the parasite degrade heme to hemozoin?

First off: The parasite must degrade hemoglobin for its survival

Next: The digestion is carried out in a vacuole of the parasitic cell; during this process the parasite releases the toxic and soluble molecule heme

But: To avoid destruction by this molecule the parasite bio crystalizes heme to form hemozoin, a nontoxic molecule; it collects in the digestive vacuole as insoluble crystals

Hemozoin is a disposal product (also called the malaria pigment)

What is wormwood? how does it serve as an alternative to quinine?

It is a Chinese herbal medicine used in fever reduction

It Produces Artemisinin (in trichomes) instead of quinine

It interacts with heme to form free radicals that kill parasites

It has a 90% efficacy rate, but there is difficulty with dealing with demand → more effective synthetic versions have been created

Risks of resistance has been approached by using combination therapies with quinine

What is the biosynthetic pathway of Artemisan like in short?

• Begins with FDP

• Pathway intermediates: IPP, DMAPP and GPP

• FPP → artemisinic acid 

• 3 oxidation steps = Artemisinin

What were the steps taken to increase artemisinin production in S. cerevisiae?

Steps 1 & 2: Increase the amount of substrate to increase FPP production 

→ modify genes related to FPP synthesis

Overexpression of tHMGR improved amorphadiene production 5X

Downregulation of ERG9 (step after FPP) using PMET3 improved amorphadiene production an additional 2X

Step 3: Find genes necessary to oxidise amorphadiene to artemisinic acid

→ isolate genes encoding enzymes responsible for oxidizing amorphadiene to artemisinic acid 

Hypothesized that the Asteraceae family plants would share common ancestor enzymes

What catalyzes the first specific hyroxylation of amorphadiene?

A cytochrome P450 monooxygenase

Where// when did absinthe originate?

• Originated in the Canton of Neuchatel in Switzerland in the late 18th century

• Mass produced at the Pernod distillery; Dr Pierre Ordinaire is credited with the first production of absinthe in 1792 as a cough medicine

• Marketed by Henri Louis Pernod as a “cure all” tonic in 1805

How is absinthe traditionally prepared?

Step 1:

• Pour 1 - 1.5 oz of absinthe in a glass

• Place an absinthe spoon over the glass

• Place a sugar cube on the spoon

• Slowly trickle 4-6 oz of water though the sugar cube into the glass

Step 2:

• After absinthe louches up (gets cloudy) dump the sugar in the glass

• Use the absinthe spoon to break up sugar and dissolve it

What are some other names for absinthe?

‘The Green Fairy’ or ‘Drink of Parisian Abandon’

Thought to infuse the drinker with creativity, intelligence and glamour

How is Vincent Van Gogh associated with absinthe?

• Cuts off his ear during an epileptic seizure – is this caused by absinthe consumption?

• He used lots of the colour yellow – is this also caused by absinthe consumption?

What was the first backlash against absinthe?

Posters warn of the dangers of absinthe!

But it was originally marketed for its extraordinary effects

It then becomes a target for prohibitionist lobby

In 1850 regular consumption causes ‘absinthism’

—> becomes a scapegoat beverage for all social ills

What is absinthism?

• Associated with epileptic seizures, orgy behaviour, sexual diseases, corrupted artists and criminals

• Mimics of absinthe sometimes contain grain alcohol and copper salts which are possibly toxic

• Scientific studies at the time show convulsions in mice due to the synergistic effects of alcohol and absinthe

What is the chronology of the absinthe ban?

• 1905 in Belgium

• 1908 in Switzerland

• 1910 in Netherlands

• 1912 in USA

• 1913 in Italy

• 1915 in France

• 1923 in Germany

What is the major compound attributed to Absinthes effects?

Thujone

What is the MOA of thujone?

• Binds to and blocks GABAa receptors in brain neurons

• GABA is an inhibitory neurotransmitter that modulates neuronal activity; GABA binds to different subtypes of receptors; GABAa is a chloride channel that is activated when bound to GABA; release of chloride into post synaptic neurons reduce synaptic activity

• Inhibition of normal GABA activity may lead to seizures seen when under the influence of thujone