Drugs Flashcards
Know the Drugs, analogs and functions.
Zidovudine
Azidothymidine, AZT
Anti-viral Nucleoside analogues – Viral reverse transcriptase inhibitors
Deoxythymidine analogue
Utilized by the viral reverse transcriptase
Upon incorporation into the double stranded DNA chain termination occurs due to lack of 3’OH
Zidovudine can:-
• Prolong life in HIV infected individuals
• Reduce mother to baby transmission by more than 20%
Didanosine (ddI)
Anti-viral Nucleoside analogues – Viral reverse transcriptase inhibitors
Deoxyadenosine analogue
Utilised by the viral reverse transcriptase
Upon incorporation into the double stranded DNA, chain termination occurs due to lack of 3’OH.
Specificity for infected cells lies in the fact that these drugs have a 100-300 fold greater affinity for incorporation by reverse transcriptase than eukaryotic DNA polymerase.
Used in the treatment of mainly HIV in combination with other anti-virals
Acyclovir
Anti-viral Nucleoside analogues – Viral DNA polymerase inhibitor
Deoxy(guanosine) analogue
Converted to the mono-phosphate by viral thymidine kinase which is much more effective in catalyzing 1st phosphorylation event than host thymidine kinase
Only infected cells possess the viral kinase
Therefore Acyclovir is only activated in infected cells.
It serves as as substrate for viral DNA polymerase.
It causes chain termination due to lack of 3’OH.
It’s 30 x more potent against viral DNA polymerase than host.
Viral kinase
High specificity for herpes simplex & varicella zoster.
Herpes simplex can causes conjunctivitis and coldsores
Tenofovir
Anti-viral Nucleotide Base analogues
Deoxyadenosine monophosphate analog
Tenofovir diphosphate competes with its natural nucleotide counterpart, deoxyadenosine 5 ́-triphosphate, for incorporation into newly forming HIV DNA.
Once successfully incorporated, termination of the elongating DNA chain ensues, and DNA synthesis is interrupted.
Cytosine Arabinoside
Cytarabine or araC
Cytosine nucleoside analogue
Ribose sugar replaced by arabinose
In cells it is rapidly converted
to cytosine arabinoside triphosphate which
acts as a substrate for several human DNA Polymerization.
AraC has a 3’ OH group to act as an acceptor for further chain elongation. However the OH gp at posn., 2 prevents polymerase adding the next dNTP due to stereo restraints causing chain termination.
Important in the therapy of leukaemias, in particular acute myeloid Leukaemia and Lymphoma (Anti cancer agent)
Adenosine Arabinoside
Vidarabine or araA
Deoxyadenosine analogue
3’OH is present but planar configuration of the arabinoside prevents DNA elongation
Uses:
Anti-neoplastic agent - Relapsed Childhood Acute Lymphoblastic Leukemia Herpes Simplex infections (Anti cancer agent)
Decitabine
(5-aza-2’-deoxycytidine)
and
5-azacytidine
Cytidine Analogues – DNA hypomethylation Agents
Deoxycytidine analogues
Once incorporated into DNA and RNA they cause hypomethylation as a methyl group cannot be added to the Nitrogen at position 5.
Additionally, these drugs are know to bind and inhibit DNA methyltransferase enzymes.
Prevents DNA methylation
In eukaryotes, methylation of cytosine is an important mechanism of transcriptional regulation.
An example of the use of DNA hypomethylating agents in Cancer….(Decitabine)
P15 Tumour suppressor gene –p15INK4b
Decitabine causes Hypomethylation
CDKN2B in a HYPOMETHYLATED promoter regions causes TRANSCRIPTION and p15INK4b prevents malignant transformation (inhibits cyclin dependent kinases)
CDKN2B in a HYPERMETHYLATED promoter regions causes TRANSCRIPTIONAL SILENCING therefore No p15INK4b transcribed= Uncontrolled cell division allowing tumor formation
Hypomethylation of CDKN2B correlates with response to decitabine
Used in Myelodysplastic syndrome & Acute myeloid leukemia
Ciprofloxacin
inhibits bacterial DNA gyrase (topoisomerase II)
quinolone drug
It is used in the treatment of respiratory and urinary tract infections and can be used to treat anthrax.
Camptothecin
Inhibitors of eukaryote replication
an anticancer drug
binds to and inhibits topoisomerase I activity whch result is DNA breakage.
Etoposide
another anticancer drug
inhibits the activity of topisomerase II (DNA Gyrase).
Actinomycin D
Dactinomycin
Inhibitors of replication
Drug- DNA complex….stable
Prevents DNA replication by:
- binds tightly to double stranded DNA preventing the formation of regions of single stranded DNA.
- Inhibits RNA transcription and replication in both prokaryotes and eukaryotes (as it prevents strand separation)
- primarily used as an anti-cancer drug (inhibiting DNA replication and cell division)
- not normally used as an antibiotic
Rifampin
- an antibiotic from a strain of Streptomyces
- inhibits initiation of transcription
- blocks formation of the first phospho- diester bond by binding to prokaryote RNA polymerase and changing its conformation
- RNA polymerase of eukaryotes is not affected
- used in the treatment of tuberculosis
Mutations in the genes encoding the target proteins such as RNA polymerase and topoisomerases can lead to drug resistance.
Alpha-Amanitin
toxin from Amanita phalloides/The Death Cap Mushroom
potent inhibitor of RNA polymerase II….which prevents mRNA transcription
There are four clinical phases of poisoning:
1) Asymptomatic phase
2) Gastrointestinal phase (1-2 days) - severe diarrhea
and vomiting
3) Apparent recovery phase - few symptoms
4) Hepatic phase - renal and liver failure
*** death may occur in 7-10 days
Treatment:
- gastrointestinal decontamination
- high dose penicillin (inhibits amanitin activity in liver)
- liver transplant
Courmarins
including Novobiocin
Inhibits bacterial gyrase (topoisomerases)
Quinolones
including Nalidixic Acid and Ciprofloxacin
Inhibits bacterial gyrase (topoisomerases)
Systemic Lupus Erythematosis
Lupus is an autoimmune disease with multiple symptoms including extreme fatigue, arthritis, fever skin rashes and kidney problems.
Individuals with this condition possess antibodies that react with the U1 RNA component of the spliceosome.
This will prevent normal splicing of mRNAs.
alternative splicing
Allows a number of different proteins to be produced from the same gene
eg: Tissue-specific isoforms Membrane bound or soluble isoforms Alternative intracellular localization Altered function
Beta-thalassemia
Mutations in genes that affect the sequence of splice donor/acceptor sites or that create new splice donor/acceptor sites can cause clinical effects:
For example, beta-thalassemia
Many individuals with beta-thalassemia have mutations in the beta- globin gene that generate additional splice sites within the mRNA.
As a result, frame shifts or premature stop codons are introduced into the mature mRNA.
This results in the production of an abnormal beta-globin protein.
Limb Girdle Muscular Dystrophy
a mutation in the calpain-3 gene that generates a new splice site within the exon 16 (coding sequence).
This results in a shorter calpain-3 mRNA that is missing exon 16 codons. This produces a defective protein.
RNA editing
RNA editing is a process in which information changes at the level of mRNA.
It is revealed by situations in which the coding sequence in an RNA differs from the sequence of DNA from which it was transcribed.
In mammalian cells there are cases in which a substitution occurs in an individual base in mRNA, causing a change in the sequence of the protein that is coded.
In trypanosome mitochondria, more widespread changes occur in transcripts when bases are added or deleted.
cytidine deaminase enzyme.
In mammals, the apo-B gene encodes two alternative forms of the apolipoprotein B: Apo-B100 (liver) and Apo-B48 (intestine).
In the intestine, the apo-B mRNA is edited so that a premature stop codon is produced (CAA
adenosine deaminase enzyme.
Glutamate receptor in the brain
Editing of the glutamate receptor involves a single base change from A to I (inosine). This editing results in a codon change within the mRNA from glutamine to arginine.
The editing affects an amino acid located in the inner wall of the ion channel and alters Ca2+ permeability. This editing is a requirement for proper brain development. This editing is accomplished by the enzyme adenosine deaminase.
Diphtheria toxin
inactivates EF-2 (elongation factor in eukaryotes)
Diphtheria bacteria become pathogenic when the bacterium itself is infected with a lysogenic phage (bacterial virus)
Diphtheria toxin enzymatically destroys E2-F which blocks translation elongation
A single molecule of diphtheria toxin may destroy all of the EF-2 proteins in the cell
Immunization protects against it
Streptomycin
Antibiotics - affect protein synthesis
Inhibition of Initiation
•An aminoglycoside
•Binds to 30s ribosomal subunit •Distorts structure •Prevents assembly of complete ribosome
Prevents initiation
Tetracycline
other family members
- Monocycline
- Doxorubicin
- Doxycycline
- etc…
Antibiotics - affect protein synthesis
Inhibitor of Elongation
- Tetracyclin blocks elongation
- 4 rings (tetra) structure
- Interacts with the 30S subunit of the complete (70s) ribosome
- Prevent the incoming aminoacyl-tRNA to access the A-site
Erythromycin
Antibiotics - affect protein synthesis
Inhibitor of Elongation
- Macrolide structure
- Binds to 50S subunit of the complete (70s) ribosome
- Blocks elongation by preventing ribosome movement relative to mRNA
- Blocks ribosome translocation
Chloramphenicol
Antibiotics - affect protein synthesis
Inhibitor of Elongation
•Inhibits prokaryotic peptidyl transferase activity (elongation)
•Not used widely in developed countries
•May inhibit mitochondrial ribosomes(translation)
• Important in some cases (i.e. some meningitis conditions)
Cycloheximide
Antibiotics - affect protein synthesis
Inhibitor of Elongation
Its a simple (relatively cheap) organic molecule that inhibits peptidyl-transferasre (elongation) in eukaryotes
-Similar mechanism to chloramphenicol
•Extremely toxic to eukaryotes (prokaryotes and mitochondria not affected)
•Widely used in laboratories (extremely cheap)
Puromycin
Antibiotics - affect protein synthesis
Inhibitor of Elongation
structural analog to a portion of the aminoacyl-tRNA
- Puromycin is toxic to both eukaryotes and prokaryotes - not clinically useful
- Puromycin blocks elongation – Peptide may form to –NH3 group, but, is then stuck
- Puromycin causes the peptide to fall out of the ribosome P-site, and causes premature translation termination
Prozac
Fluoxetine
- antidepressant drug that blocks serotonin elimination from synaptic cleft.
•Serotonin re-uptake inhibitor
• Enhances the action of the neurotransmitter.
Lysergic acid diethylamide (LSD)
Lucy in the sky with diamond
-affects serotonin receptors that are located in the brain stem.
Allopurinol
-used for treatment of gout in patients who are “overproducer” of uric acid.
Allopurinol inhibition of xanthine oxidase
can be described as suicide inhibition
as the drug itself is used as substrate for xanthine oxidase and then modified to an irreversible inhibitor.
The newly formed alloxanthine (oxypurinol) interferes with the cofactor molybdenum that is needed for xanthine oxidase itself.
