PaBi (10): Drug development- trypanosomiasis

Question 1

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

Answer 1

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

Question 2

How do these drugs need to be administered?

Answer 2

Intravenous or intramuscular- requires hospitalisation

Question 3

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

Answer 3

Early= suramin 
Late= melarsoprol

Question 4

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

Answer 4

Early= pentamidine
Late= eflornithine

Question 5

What are the effects of suramin?

Answer 5

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

Question 6

How does pentamidine work?

Answer 6

Accumulates in the parasite and interacts with DNA and inhibits enzymes

Question 7

What is the downside of melarsoprol?

Answer 7

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

Question 8

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

Answer 8

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

Question 9

What are the four different purine transporters?

Answer 9

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

Question 10

What transporters take up pentamidine and melarsoprol?

Answer 10

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

Question 11

What is the function of trypanothione in the parasite?

Answer 11

It mops up free radicals eg hydrogen ions

Question 12

How does efluornithine act to target trypanothione synthesis?

Answer 12

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

Question 13

What parasite strain is treated by efluornithine and why?

Answer 13

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

Question 14

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

Answer 14

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

Question 15

What are some drug resistance mechanisms?

Answer 15

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

Question 16

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

Answer 16

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

Question 17

What is a benefit of genome sequencing for drug targeting?

Answer 17

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