PaBi (10): Drug development- trypanosomiasis Flashcards

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1
Q

Why are different drugs used to treat stage 1 and stage 2 of infection with trypanosomes?

A

Because in stage 2 the parasite has crossed the blood-brain barrier

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2
Q

How do these drugs need to be administered?

A

Intravenous or intramuscular- requires hospitalisation

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3
Q

What drugs are used to treat T b rhodiense early and late stage infection?

A
Early= suramin 
Late= melarsoprol
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4
Q

What drugs are used to treat T b gambiense early and late stage infection?

A
Early= pentamidine
Late= eflornithine
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5
Q

What are the effects of suramin?

A

Inhibit thymidine kinase and all glycolytic enzymes in parasite but can also have an effect on mammalian cells so has life threatening side- effects

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6
Q

How does pentamidine work?

A

Accumulates in the parasite and interacts with DNA and inhibits enzymes

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7
Q

What is the downside of melarsoprol?

A

Main ingredient in arsenic, 2-3% of people die from the drug (but would die from parasite anyway)

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8
Q

Why do trypanosomes need purine transporters and how do drugs target it for uptake?

A

They can’t synthesise adenine and guanine so they need to transport it from the host so some drugs are taken up by these transporters by competing with A and G

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9
Q

What are the four different purine transporters?

A

P1 and P2- low affinity, H2 and H3- high affinity

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10
Q

What transporters take up pentamidine and melarsoprol?

A

P1, P2 and AQP2, because they are structurally similar to purines

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11
Q

What is the function of trypanothione in the parasite?

A

It mops up free radicals eg hydrogen ions

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12
Q

How does efluornithine act to target trypanothione synthesis?

A

It binds irreversibly to ornathine decarboxylase. This prevents the synthesis of spermidine which holds two glutathione molecules together, making trypanothione.

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13
Q

What parasite strain is treated by efluornithine and why?

A

T. b. gambiense because the half life of ornathine decarboxylase is very long (>18hrs) compared to rhodiense (~4hrs) which has a lot more ODC, so gamiense can be eliminated by the immune system once treated

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14
Q

Why does efluornithine not have much of an effect on human ODC even though it binds?

A

The half life of human ODC is much shorter (~20mins) so more is produced

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15
Q

What are some drug resistance mechanisms?

A

Decreasing drug levels e.g. preventing drug influx, increasing drug efflux, blocking drug by binding them with molecules, sequestration into vesicles, blocking activation of pro-drug. Changes to the drug target e.g. decreased affinity, increased damage repair

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16
Q

What are the essential factors that make a parasite feature a viable drug target?

A

It is a function essential for the growth of the parasite, differs from host cell features i.e. no/ non-essential feature in the host, and there is differences in accumulation e.g. host has export mechanisms, parasite has activating enzyme

17
Q

What is a benefit of genome sequencing for drug targeting?

A

You can identify genes which are shared between parasite species for cross-specific drug targeting