Lecture 2 Flashcards
How can you define selective toxicity at a biochemical level?
- Drug target unique to the parasite, e.g. dhps in plasmodium
- Drug target with different structure and specificity in parasite and host, e.g. benzimidazoles for helminth beta-tubulin
- Drug target activity in bost host and pathogen but effect on host not significant becuase of alternative pathways or high mammalian ezyme turnover, e.g. pyruvate kinase
- Acitve drug is formed by metabolism only in parasite but not in host, e.g. 5-nitroimidazoles; in anaerobic pathogens d
How can you define selective toxicity at a cellular level?
- Drug only penetrates the parasite, due to different membrane composition
- ## Drug uptake and localisation affected if parasite intracellular
How can you define selective toxicity at the level of the host?
-Pharmacokinetics; how the drug affects the body
What must be considered for pharmacokinetics?
- Route of administration
- Adsorption
- Distribution
- metabolism
- Excretion
- Interaction with immune system
What are the key characteristics of an Antiparasitic drug target?
- Essential for parasite growth or survival in the host
- Selective inhibition possible with small molecules
- Amenable to study at the molecular level
What drugs target DHPS?
Sulphonamide drugs, e.g. sulphadoxine
What role does DHPS play in plasmodium?
Important in folate synthesis
How was DHPS validated as a drug target?
Created Plasmodium falciparum mutants with resistance to sulphadoxine due to point mutants. Transgenic P. falciparum with mutant DHPS alleles - correlated with different levels of sulphadoxine resistance
Which unique enzyme is a possible target to treat the Kinetoplastids?
Trypanothione reductase; removal of toxic oxygen radicals. 40% amino acid identity same as human variant but different enough to be targeted. Still no viable inhibitors have been found.
Give two example enzymes that are found in both host and parasite that could be targeted for treatment
1) DHFR-TS
2) NMT
What drug inhibits DHFR-TS? Why is it used on hosts?
Methotrexate
Treat arthritis, immunosuppressant and for cancer
How effective has methotrexate been in treatment of Leishmania?
In vivo activity disappointing - due to alternative folate synthetic pathway
Give an example of a piggy-back taregt
N-myristoyltransferase (NMT) inhibitors
Originally being developed for the treatment of pathogenic fungi but meant that all tools in place to study for treating parasite.
NMT is an enzyme that catalyses co-translational N-terminal addition of myrisitic acid to cellular proteins; aids sub-cellular targetting. NMT expression is essential for parasite viability in trypanosomatids.
Outline the mode of action of metabolomics
1) Metabolites are grown in the presence and absence of drug
2) Metabolism is quenched, usually by rapid cooling in a dry ice ethanol bath for paraites
3) Medium is removed and metabolites extracted
4) Metabolites chromatographically separated
5) Metabolites detected using UV, mass spec or NMR
Which drugs has metabolomics been shown to be effective in treating T. brucei?
Eflornithine, an ornithine decarboxylase (ODC) inhibitor
Nifurtimox, thought to be involved in DNA an RNA degradation
5-fluoroorotic acid and 5-fluorouracil, thought to degrade RNA
5-fluoro-2′deoxyuridine and 5-fluoro-2′deoxycytidine, inhibits the bifuntional dihydrofolate reductase-thymidylate synthase enzyme, leading to a large increase in dUMP
