Chapter 10: Miscellaneous Drug Targets Flashcards
How can transport proteins act as drug targets?
The binding site for the molecule being transported has a drug bind it and therefore prevent transport
What are two examples of drugs that bind to transport proteins and what is their effect on the body?
Cocaine and tricyclic antidepressants
bind to transport proteins and prevent neurotransmitters (e.g., noradrenaline, dopamine) from re-entering nerve cells
_______ acts centrally to inhibit the reuptake of serotonin, noradrenaline and, to a lesser extent, dopamine. The increase in serotonin results in?
Sibutramine,
Increase in serotonin = dulls appetite
What 6 antidepressant drugs act on transport proteins to block the uptake of serotonin?
Fluoxetine (prozac) Citalopram EScitalopram Sertraline Paroxetine Fluvoxamine
Enfuvirtide (HIV fusion inhibitor) can be used to prevent _______ assembly or viral entry into a cell
Capsid (outer protein shell of virus)
What are the two drugs that inhibit tubulin polymerization
colchicine – used in the treatment of gout
Vinca alkaloids derived from periwinkle plant – anticancer agents
ie, vincristine, vinblastine, vindesine and vinorelbine
What drug and its analog inhibit tubulin depolymerization?
paclitaxel (Taxol) and the semi-synthetic analogue, docetaxel, are important anticancer agents
How can drugs take advantage of the transport across the cell membrane
Polar molecules cross the hydrophobic cell membrane, therefore . drugs can be designed to take advantage of this transport system in order to gain access to cells or to block the transport protein.
____ is structural protein crucial to cell division and cell mobility and is the target for several anticancer drugs.
Tubulin
How do the Vinca alkaloids work to effect tubulin?
The Vinca alkaloids bind to tubulin and inhibit the polymerization process.
How does taxol work to effect tubulin?
bind to tubulin and accelerate polymerization by stabilizing the resulting microtubules
What is the one biosynthetic building block as a drug target?
Vancomycin
What does vancomycin inhibit?
inhibits proper cell wall synthesis in Gram-positive bacteria
How does vancomycin work?
large hydrophilic molecule is able to form hydrogen bond interactions with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides
Crystal structure of a short peptide L-Lys-D-Ala-D-Ala
What is the one biosynthetic process (chain terminator) as a drug target?
Puromycin
What effect does puromycin have?
terminates polypeptide elongation during protein translation
True or False: Puromycin enters the B site of the ribosome and assists aminoacyl-tRNA molecules to bind
False, enters the A site of the ribosome and prevent aminoacyl-tRNA molecules from binding
How does the transfer of the peptide chain to puromycin work?
NH2 group attacks Carbon group, NH becomes bound to peptide group and double bond O
leaving OH group on aminoacyl-tRNA
What are the two examples of antibodies that can inhibit protein-protein interactions?
daclizumab
abciximab
_____ is a human monoclonal antibody that was developed as a immunosuppressant in kidney transplants (discontinued) to treat adults with relapsing forms of MS
daclizumab
What is the effect(s) of abciximab?
inhibits blood clotting following angioplasty by preventing platelets from sticking together and causing thrombus (blood clot) formation within the coronary artery
Describe the interaction between MDM2-p53
Normally: MDM2 binds to p53, MDM2 ubiquitinates p53 resulting in p53 leaving nucleus. P53 degradation is mediated by MDM2 in the cytosol
What 5 things cause p53 to activate?
DNA damage Telomere damage Oncogene Ribonucleotide depletion Oxidative stressor hypoxia
What are the 6 hallmarks of tumors that enable them to survive?
Resisting cell death Evading growth suppressors Sustaining proliferative signalling Activating invasion and metastasis Enabling replicative immortality Inducing angiogenesis
RESAEI
True or False: Overexpression of MDM2 promotes the development of the malignant phenotype
True
MDM2 functions as E3 ligase (assists in transfer of ubiquitin), moves p53 to cytosol to be degraded by proteolytic enzymes,
MDM2 inhibits transcriptional activity of p53
True or False: Inhibition of MDM2 allows for restoration of p53 tumour suppressor function
True
_____ are a series of cis-imidazoline analogues that are a important negative regulator of the p53 tumour suppressor
Nutulins
How do nutulins work?
mimic 3 amino acids (amino acid finger) present on p53 (Leu-26, Trp-23, Phe-19) and prevent the interaction mdm2 and p53
True or False: Nutlin binds in the same cleft as the native p53 helix.
True
____ as drug targets generally act by disrupting cell membrane structure
Lipids
____ is used topically against athlete’s foot and systemically against life-threatening fungal diseases
Amphotericin B
How does amphroectin B work?
interacts with the lipids and sterols (ergosterol) of fungal cell membranes to build ‘tunnels’ through the membrane
How does Gramicidin work against the lipid membrane?
thought to coil into a helix such that the outside of the helix is hydrophobic and interacts with the membrane lipids
the inside of the helix contains hydrophilic groups
this allows the leaking of ions from the cell leading to cell death
Gramicidin D is a heterogenous mixture of three antibiotic compounds, , gramicidins A, B and C, making up ______, ______, and ______, respectively
80%, 6%, 14%
peptide antibiotics with 15 alternating l- and d-amino acids
______ allow molecules to leach out from the cell and cause cell death
Nanotubes
True or False: cyclic peptides which will self-assemble in the cell membranes of bacteria to form tubules
True
How do nanotubes work?
6 to 8 alternating d- and l-amino acids such that the amide groups are perpendicular to the plane of the cyclic structure, with the side chains pointing outwards in the same plane
Why is valinomycin known as a natural neutral ionophore?
does not have a residual charge
____ is a dodecadepsipeptide made of 12 alternating amino acids and esters to form a macrocyclic molecule
Valinomycin
True or False: Valinomycin is obtained from the cells of several Streptomyces strains
True
A ____ ion sits in the _____ centre of valinomycin
Potassium, hydrophillic
How does valinomycin disrupt the cell?
Valinomycin kills bacteria by facilitating the transport of K+ ions across the cell membrane, thereby disrupting the normal distribution of ions in the bacterium
True or False: the K+–valinomycin complex is highly soluble in the nonpolar interior of the membrane
True
________ and ______ act on the plasma membrane and result in the uncontrolled movement of ions across the cell membrane leading to cell death.
‘Tunnelling’ molecules, ion carriers
________ are being designed which will self-assemble to form nanotubes in the cell membranes of bacteria.
Cyclic peptides
How can carbohydrates as drug targets be used to fight against cancers?
antibodies in the treatment of cancer by producing antibodies which will target carbohydrate-containing antigens that are overexpressed on the surface of cancer cells
can be used by themselves to mark cancer cells for destruction or as a means of delivering anticancer drugs to cancer cells
the interior of cyclodextrins is relatively _______ and can accommodate drug-sized molecules
hydrophobic
have been extensively studied as a means of drug delivery for hydrophobic drugs
sugammadex, a cyclodextrin that acts as a _______ for rocuronium, a neuromuscular blocker used in modern anaesthesia
‘scavenger’
