Inflammatory Drug Targets Flashcards
Describe the MOA of corticosteroids involving GATA-3.
- GATA-3: TH2 transcription factor essential for gene expression of IL-4, IL-5, and IL-13 cytokines that mediate allergic inflamation (also inhibits T-bet via STAT-4)
- Normally in cytoplasm, but when activated by APCs via TCR CD3 and CD28, GATA-3 is phosphorylated by p38 MAP kinase and translocates to nucleus via importin-alpha (a nuclear import protein)
- Corticosteroids bound to glucocorticoid
receptors inhibit GATA-3 function by competing for nuclear entry via importin-alpha and by inhibiting p38 MAP kinase through induction of MAP kinase phosphatase-1 - Corticosteroids act as indirect inhibitors
What is the MOA of Omalizumab (Xolair)?
- An anti-IgE antibody that prevents IgE from binding to mast cells in an attempt to reduce the likelihood of histamine release.
- Reserved for hard-to-treat cases
- Has to be injected, and expensive
What is the MOA of Roflumilast?
- Approved for the tx of COPD
- Selectively inhibits phosphodiesterase-4 (PDE-4) enzyme, blocking the hydrolysis and inactivation of cAMP, and resulting in intracellular cAMP accumulation
- Thought to decrease inflammatory activity (by relaxing airway smooth muscle and inhibiting its proliferation, suppressing inflammatory cell function), although mechanism is not fully understood
- This medication is not a bronchodilator
What are the traditional anti-inflammatory drug therapies?
What is the limitation to these therapies?
NSAIDS
and
Corticosteroids
nonspecific and sometimes ineffective
Explain the benefits of TNF-alpha.
Why is TNF-alpha a drug target?
Why are TNF-a inhibitors helpful?
TNA-alpha helps with immune surfeillance, tumor regression, innate immunity, protection from bacterial infection and hematopoiesis.
- TNF-a is a drug target because dysregulation can lead to various diseases
- Can control the disease process by mediating level of TNF-alpha
What are the 7 potential targets for drug therapy in targeting inflammation?
(Hints: Nucleus, cytokines, signaling)
1) Blocking synthesis of cytokines from DNA (corticosteroids)
2) Blocking transcription factors regulating cytokine expression (calcineurin inhibitors and decoy oligonucleotides)
3) Blocking secreted cytokines with antibody blockers (Anti-interleukin IL-5 antibody)
4) Blocking secreted cytokines with soluble receptors (IL-4 soluble receptor)
5) Blocking cytokine receptors (chemokine receptor antagonists)
6) Blocking signal transduction pathways (p38 mitogen activated protein kinase inhibitors)
7) Blocking transcription factors activated by cytokines (STAT6 inhibitors)
What type of mechanism do corticosteroids use ?
transcriptional regulation inhibitor
Corticosteroids inhibit GATA-3 (transcription factor) by competing with activated GATA-3 for entry into nucleus via “importin-alpha”.
Corticosteroids also induce formation of MAP kinase phosphatase-1 which inhibits p38 MAP kinase (necessary kinase for activating GATA-3)
Remember, corticosteroids are phospholipase inhibitors.
[[[GATA-3 (transcription factor) for development of Th2 cells to differentiate and produce IL-4, IL-5 and IL-13. These mediate allergic inflammation.]]]
This inhibits production of IL-4, IL-5 and IL-13
What is the drawback corticosteroids?
They have indiscriminate effects that can sometimes be deleterious to the patient’s health.
Adverse effects accompany use of these drugs because of additional pathways associated with these blocked transcription factors.
This becomes most notable after extended use of corticosteroids.
Corticosteroids indiscriminately block mutiple pathways including GATA-3 transcription factor and NF-kB. Here is a insanely loaded line of questions….
Describe the normal activation of NF-kB
How do corticosteroids inhibit NF-kB?
What effect will this have on the cell?
When you are done, bury your head in the sand and weep.
Describe the normal activation of NF-kB.
- IL-1 and TNF-a activate receptors or TLRs on cell surface
- IkB kinase is activated (IkB is a natural inhibitor of NF-kB = keeps it inactive in cytoplasm)
- IkB kinase phosphorylates IkB, causing ubiquination, releasing it from NF-kB and IkB gets degraded by a proteosome
- NF-kB is free to move into nucleus to activate RNA transcription => cytokines and shit.
**How do corticosteroids inhibit NF-kB? **
- Inhibit importation of NF-kB into nucleus and inhibit phosphorylation of IkB - Somehow. Mechanism not fully understood
What effect will this have on the cell?
- down regulate gene expression of many pathways. Indiscriminate.
What type of mechanism do NSAIDs use ?
Cytokine synthesis inhibitors
Inhibit COX-1 and COX-2 reversibly except acetylsalicyclic acid (ASA)
What type of mechanism does Zileuton use ?
Leukotriene synthesis inhibitor
What type of mechanism do Adalimumab (Humira) and Certolizumab (Cimzia) use ?
Soluble cytokine receptor
Blocking monoclonal antibody
What type of mechanism do anti-histamines use ?
receptor blockers
What type of mechanism does montelukast (Singulair) use ?
receptor blockers
Describe the complexity of treatment of asthma patients in regards to drug regimen choices.
Why are anti-histamines unhelpful for chronic asthma?
Asthma pathology includes bronchospasm and inflammation.
Histamine is released and causes bronchospasm.
Histamine stimulates synthesis of inflammation mediators such as: PAF, LT, PGD2, ECP, MBP, Proteases, PAF
These cause remodeling of lung tissue over time if not treated.
Anti-histamines block histamine binding to H1 receptors but do not prevent release of histamine from mast cells.
