Vl 2 - drug discovery Flashcards
African sleeping sickness: pathogen ,vector, symptoms
- trypanosoma brucei
- Vector: Tsetseflies
- Initial symptoms: fever, headaches, joint pains, and itching, swollen lymph nodes
- disruption of sleep-cycle, confusion, tremor, paralysis
⇒ fatal within months
River Blindness: Pathogen, vector, symptoms
- Onchocerca volvulus
- Vector: blackflies
- Motile male
- female worms produce 100s of microfilariae/ day
- Chronic papules, depigmentation, skinatropy, glaucoma, blindness
- O. volvulus depends on symbiotic Wolbachia
Suramin
- Highly toxic against cells
- Mode of action unknown (NADH, P2 receptors)(epigenetic influence against antigen variation?)
Leishmaniasis: pathogen, vector, symptoms
- leishmania spp.
- vector: sandfly
- invades macrophages
- fever, weight loss, fatigue, anemia, and substantial swelling of the liver and spleen
- Fatal if untreated
- Chronic
Pentavalent Antimonials
- pentavalent antimony compound urea stibamine and sodium stibogluconate
- Active and still recommended against visceral Leishmaniasis
- Intramuscular injection
- Strong side-effects: pot. fatal cardial arrythmia, increased mortality in HIV patients
- Threatened by resistance in India
- Mode of action unclear: via toxic trivalent Sb or complexation with ribose-derivatives
Babesiosis: pathogen, vector, symptoms
- Babesia spp.
- vector: ticks
- infects red blood cells ⇒ haemolysis, fever, weight loss
Pentamidine
- against african sleeping sickness, leishmaniasis, babesiosis
- mild side-effects
- Threatened by resistance
- Needs to be injected/inhaled, does not cross blood brain barrier
- Mode of action unclear, involves crosslinking adenines and inhibition of topoisomerases
Pyrimethamine
- against Malaria (but extensive resistance)
- Active against Toxoplasma gondii
- Clear mode of action, anti-folate, DHFR-TS
- Use in research as a selection marker
- Serious side effects
Ivermectin
- active against: head lice, scabies, river blindness, strongyloidiasis, trichuriasis, and lymphatic filariasis
- mode of action clear: binds glutamate-gated chloride channel
why are parasitic diseases often neglected?
- drug component development often too expensive to be worth it for companies
2 diseases (and their pathogens) which can be treated with suramin
- sleeping sickness: t.brucei (vector: tsetse fly)
- river blindness: Onchocerca volvulus (vector:black fly)
what does the pathogenicy of o. volvulus depend on?
- symbiotic wolbachia bacteria
how can sleeping sickness and river blindness be treated?
Suramin
- highly toxic, mechanism unknown (inhibits epigenetic machinery?), NADH and P2-receptors involved
how can Leishmania be treated? mechanism?
sodium stibogluconate
- vs visceral leishmaniosis, strong side effects (potenial heart arrythmia)
- mode of action unknown: via toxic trivalent Sb or complexation with ribose-derivatives.
how are leishmaniosis, trypanosomiasis and babesiosis treated?
- Pentamidin: mild side effects, mode of action unknown
- involves cross linking adenines and inhibition of topoisomerases.
- resistances in babesiosis
- in trypanosoma only effective if not in neurological tissues (e.g. central nervous system)
what kind of malaria is caused by p. falciparum? how was it first treated? mechanism?
Malaria tropica
- Quinine: basis of Chloroquine. Isolated from cinchona bark. vs Babesia and Plasmodium
- mechanism: presumably disrupts hemoglobin metabolism by interfering with heme detoxification by hemozoin crystals.
- Chloroquine: 1st blockbuster drug vs Plasmodium -> massive side effects (damage of vision, muscles, low rbc levels) -> extensive resistances developed
which cells are attacked by toxoplasma? how many humans are affected worldwide?
- all cells with a nucleus in warm blooded animals
~1/3 of humanity permanently infected
how is toxoplasma treated? what was the drug used for previously?
Pyrimethamin
- exact mode of action unknown: antifolat, dihydrofolatreduktase enzyme inhibition, strong side effects
- previously used vs malaria, but extensive resistances developed
2 anti parasite drugs with known mechanisms
Pyrimethamin and Ivermectin
- Pyrimethamin: exact mode of action unknown: antifolat, dihydrofolatreduktase enzyme inhibition. strong side effects
- Ivermectin: vs river blindness and lymphatic filiariose
- binds glutamate-gated chloride channel
process of drug development? costs for a new drug?
Stage 1: Drug discovery (~ 10000 components tested).
Stage 2: pre-clinic development (250 components).
Stage 3: clinic development (5 components):
Phase 0: effect in the body
Phase I: safety in humans
Phase II: efficacy of disease treatment (what barriers can the drug pass?)
Phase III: large scale safety and efficacy?
Phase IV: long term safety
regulatory approval
whole process costs ~0,7-2,7 billion US-dollars per drug
typical approaches to drug development? exsample
- Target-based approach:
Essential genes ⇒ Structure-guided inhibitor design ⇒
in vitro SAR optimization ⇒ Cell-based tests ⇒ Animal and clinical studies ⇒ approval
BUT: Very high drop-out rates, Expensive - Phenotypic screen-based approach:
Screen for parasiticial hits ⇒ hit-to-lead optimization ⇒
Further animal and clinical studies ⇒ approval
BUT: inefficient optimisation and high toxicity
what drug us suited to treat which disease/eradicate which parasite?
- Suramin: river blindness and african sleeping sickness
- Ivermectin: river blindness and
lymphatic filariosis - pentavalent antimonials ⇒ today Sodium stibogluconate: leishmaniosis
- Pentamidin: leishmaniosis, sleeping sickness and babesiosis
- Quinine: malaria, babesiosis
- Pyrimethamin: toxoplasmosis, (previously Malaria)
