Drug Development Flashcards
Define drug development
Process of bringing a new pharmaceutical drug to the market
Outline the four main stages of the drug development model
- Drug discovery
- Pre-clinical development
- Clinical development
- Regulatory approval
How many phases are there in clinical development
- Effect on body
- Safety in humans
- Effectiveness at treating diseases
- Larger scale safety and effectiveness
- Long-term safety
Roughly how long does drug development take
12-15 years
Define druggability
The ability of a protein target to bind small molecules with high affinity
What proportion of the human genome is draggable
10-15%
What four key structures are interacted with by drugs
- G protein coupled receptors
- Nuclear hormone receptors
- Ion channels
- Kinases
Name examples of where we can find drugs
- Medicine from plants
- Inorganic elements
- Organic molecules
- Bacteria
- Stereoisomers
- Immunotherapy antibodies
- Gene therapy
What plant alkaloid is morphine extracted from
Poppy
What plant alkaloid is atropine extracted from
Deadly nightshade
What plant alkaloid is vincristine extracted from
Periwinkle
Name on anaesthetic
Isoflurane
Name an antiseptic
Chlorhexidine
What does Humira monoclonal antibody target
TNF alpha
When is Infliximab prescribed
Rheumatoid arthritis
How does Infliximab effect rheumatoid arthritis
Chemical inhibition by extracellular neutralisation of TNF alpha
Inhibits lymphocyte proliferation
How is Infliximba delivered
Every 6-8 weeks
Structure of Etanercept
Dimeric fusion protein of TNF type II receptor
When is Etanercept prescribed
Rheumatoid arthritis and psoriasis
What are infliximab and etanercept examples of
Chimeric antibodies
What is an example of a human antibody used for pharmaceutical treatments
adalimumab
How does Adalimumab
Inhibits lymphocyte proliferation, down regulates inflammatory reactions associated with autoimmune disease
How is adalimumab injected
Subcutaneously - fortnightly
Why is IgG not filtered by the kidney
Too big molecular weight
Role of FcRn receptors
Systemic receptors which absorb IgG into cells protecting them from metabolism
Problem with using mouse antibodies for human FcRn
Shorter half-life than human antibodies
The three step process in Zmapp production for Ebola treatment
- Mouse genes extracted from hybridomas
- Chimeric conversion to humanised gene
- Transfect with viral vector into tobacco plant
What iz ZMapp’s structure
THREE chimeric monoclonal antibodies
Stturtcure of insulin
2 peptide chains joined by disulphide bridges derived from a single sequence of proinsulin
Describe recombinant human insulin process
- Plasmid isolated from bacterial cell
- Restriction endonuclease recognises specific site
- Break DNA to give sticky ends
- Same enzyme cuts out gene of interest from human DNA
- Ligase joins the two pieces together by complementary base pairing (forms phosphodiester bonds)
- Bacteria secrete insulin and it’s collected
How does Insulin Lispro function and made
Made: Switches lysine and proline residues
Function: and prevents insulin dimer formation
Why do we use Insulin Lispro
Faster onset, shorter duration of action
Inject before a meal
How is slow insulin produced
Protein binding: Substitute lysine (B29) with myristic acid binds to albumin
Micro crystals: Asparagine substitution with glycine + 2 Arginines. Aggregates due to neutral pH following subcutaneous injection
Half-life of protein binding long acting insulin
5-8 hours
When are micro crystals soluble
Acidic pH
Half-life of slow release insulin produced as micro crystals
18-24 hours
What is the advatanage of long acting insulin
Lower risk of nocturnal hypoglycaemia
Problems of long-acting insulin
Mammary tumours
Adverse effects of mineralocorticoids
- Hypertension
- Fluid retention
- K/Ca loss
Adverse effects of glucocorticoids
- Diabetes
- Osteoporosis
- Muscle wasting
- Peptic ulcers
Role of Calcineurin
Phosphatase enzyme which activates NF-AT (T cell activation precursor)
How does Nf-AT activate T cells
Binds to promotor site for IL-2 transcription
Role of IL-2
Lymphocyte activation
When are calcineurin inhibitors given
Skin inflammation
Name two calcineurin inhibitors
Ciclosporin
Tacrolimus
What can folic acid deficiency lead to
Anaemia and worsens leukaemia
Role of methotrexate
Inhibits dihydrofolate reductase to increase levels of folate in blood
Why is THf important
Required to incorporate carbon atoms to form purine rings and precursor of guanine and adenine bases
How do azathioprine work
Blocks incorporation of thiopurine analogues into the DNA structure, causing chain termination and cytotoxicity
How do cyclophosphamide work
Causes irreversible DNA cross-links = apoptosis
Name a protein kinase inhibitor
Vemurafinib
What three ways does gene therapy prevent disease
- Replacing mutated genes
- Inactivating a mutated gene
- Introducing a new gene in th body
Result of Lipoprotein lipase deficiency
Cause severe pancreatitis
How do we treat lipoprotein lipase deficiency
Glybera delivers intact copy of human lipoprotein lipase gene
How is Glybera delivered for treatment
Delivered to non-diving cells
How does high-throughput creeping work
Compares results to libraries of thousands of compounds
Define rational drug design
Process of dining new medications based on the knowledge of a biological target
What does rational drug design rely on
- Computer modelling techniques
2. Knowledge of 3 dimensional structures of the bimolecular targett is known as a sturcture-absed drug design
