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53 Cards in this Set
- Front
- Back
Describe antisense therapy for mRNA interference
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When does Rnase H cleave RNA?
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When initiated by oglionucleotide
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Ribonuclease (commonly abbreviated RNase) is a type of nuclease (nuclease = enzyme that cleaves phosphodiester bonds) that catalyzes what?
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the degradation of RNA into smaller components
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During normal DNA replication, RNase H is responsible for removing what? This allows for what?
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the RNA primer, allowing completion of the newly synthesized DNA.
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Rnase has what kind of mechanism?
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Rnase has a hydrolytic mechanism. It has a classification EC 3.1.26.4
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What is transcription?
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Transcription – antisense oligonucleotide initiates degradation of mRNA strand
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What is Capping?
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antisense oligonucleotide prevents further expression of RNA into protein
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What is splicing and translation?
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antisense oligonucleotide prevents further splicing and blocks translation
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The siRNAs are generated from what?
The siRNA is then incorporated into what? What does it guided? What happens from there? |
ong, double-stranded RNA molecules processed by an enzyme called "Dicer”
into RNA-induced silencing complex (RISC), which guides a nuclease (Rnase H) to the target mRNA, which is subsequently degraded, thus blocking protein synthesis. |
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The structure of siRNA consists of what strands and what nucleotides? What is essential for RISC docking?
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Two strands designated “guide” and “nonguide”
Two nucleotide 3’ “overhangs” and 5’ phosphates present 5’ phosphorylation essential for RISC docking |
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What 4 things do conventional drug targets?
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1) gene regulation; alter mRNA expression (e.g. fibrates, glitazones) inside nucleus.
2) Inhibit protein synthesis (some antibiotics). 3) Alter post translational protein processing. 4) Direct agonist or antagonist with a specific protein. |
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What are two steps insiRNA therapy?
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1) siRNA mediated cleavage of mRNA
2) Degradation of the mRNA fragments |
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siRNA mediates selective cleavage of what? Specificty is determine by what?
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siRNA mediates selective cleavage of specific mRNA
Knock-down of a specific protein Specificity is determined by siRNA sequence. |
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What Improves Stabilityof Oligonucleotides?
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Backbone modifications
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What are 4 first generation backbone modifications?
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What are second generation backbone modifications?
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What is the first marketed antisense therapeutic agent (cytomegalovirus inhibitor?
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Fomivirsen
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What are 3 Various Delivery Technologies that Can Potentially be Used for siRNA Delivery?
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Naked siRNA(with or without targeting agentslike cholesterol)
Stable Nucleic Acid–Lipid Particles (SNALPs) Lipid Nano Particles (LNPs) |
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What are 4 subcategories (type of neurotransmitter)
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1. Cholinergic (acetylcholine)
2. Adrenergic (noradrenaline/norepinephrine) 3. Serotinergic (serotonin) 4. Amino Acid |
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Nervous System = ?
Central Nervous System =? Peripheral Nervous System=? |
Nervous System = CNS (Central) + PNS (Peripheral)
Central Nervous System = Brain and Spinal Chord Peripheral Nervous System = sensory neurons (informs CNS of stimulus) + motor neurons (“effectors” running to muscles and glands that take action) |
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The PNS is divided into what two components?
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The PNS is divided into somatic and autonomic components.
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Somatic Nervous System gives us what? It has what to react to external stimulus? How many pairs of cranial nerves and spinal nerves? All of the spinal nerves are what?
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gives us conscious awareness of the external environment
also has the motor neurons to react external stimulus has 12 pairs of cranial and 31 pairs of spinal nerves all of the spinal nerves are mixed sensory/motor neurons |
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In Autonomic Nervous System What neurons that run from the CNS to major organs in the body?
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Sensory and motor
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In ANS What two sets of motor neurons are present?
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preganglionic arise in the CNS and run to a ganglion, where they synapse with the postganglionic neurons that run to the effectororgan
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What are 2 subdivisions of ANS?
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sympathetic and parasympathetic
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In Sympathetic Nervous System preganglionic neurons arise where? and go to where?
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in spinal chord and go to sympathetic ganglia on each side of the spinal chord
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In the Sympathetic Nervous System what 3 things may neurons do?
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the neuron may 1.) connect with postganglionic neurons 2.) run up or down sympathetic chain and synapse higher or lower in the body or 3.) leave the ganglion to a special ganglion synapse in the viscera or connect directly to the highly specialized secretory portion of the adrenal medulla
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In the Sympathetic Nervous System the neurotransmitter released by the preganglionic neurons is what?
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is acetylcholine
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In the Sympathetic Nervous System the neurotransmitter released by the postganglionic neurons is what?
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noradrenaline (also called norepinephrine)
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noradrenaline may be what to particular gland or muscle?
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excitatory or inhibitory
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stimulation of the sympathetic branch of the of the autonomic nervous system id responsible for what reflex?
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fight or flight
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the release of adrenalin from the adrenal medulla ensures what?
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that all cells of the body will be exposed to sympathetic stimulation even when no postganglionic neurons reach them directly
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In the Parasympathetic Nervous System, what is the main nerve? where is it originated from?
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the main nerves are the vagus nerves, originating in the medulla oblongata
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In the Parasympathetic Nervous, each preganglionic parasympathetic neuron synapses with what? Where are they located?
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just a few postganglionic neurons which are located near or in the effector organ/muscle/gland
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In the Parasympathetic Nervous what is the neurotransmitter for the pre-and most of the post-ganglionic neurons? Some postsynaptic neurons release what?
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acetylcholine
Some postsynaptic neurons release nitric oxide as their neurotransmitter |
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the parasympathetic system reverses what?
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reversing the physiologic effects of “fight or flight”
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In Parasympathetic Nervous System the vagus nerve releases what? Why?
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the vagus nerve reverses inflammation also, since acetylcholine suppresses the release of inflammatory cytokines in inflamed tissues
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Cholinergic means what?
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Neurons that Release Acetylcholine
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Cholinergic is further subdivided into what? depending on their ability to what?
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into muscarinic and nicotinic depending on their ability to bind the naturally occurring alkaloid muscarine or nicotine
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chemical compounds that cause stimulation of the parasympathetic nervous system are called what?
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cholinomimetic or, more specifically, parasympathomimetic agents.
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cholinomimetic agents might be agonists that act directly on what? They might function as what?
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on cholinergic receptors or function as inhibitors of acetylcholinesterase (AChE), the enzyme responsible for hydrolysis of acetylcholine
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acetylcholine is widespread in what system?
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autonomic nervous system, and imbalanced parasympathetic tone has serious physiological consequences
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many synthetic cholinergic agonists have been designed using what?
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structure–activity relationships (SARs) based on the structure of acetylcholine
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What are Muscarinic Receptors subtypes? What kind of receptors are they?
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subtypes designated M1-M5 and high subtype selectivity is rare.
g -protein coupled receptors |
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Nicotinic Receptors are found at what 3 sites? What are they classified as? What does the receptor create? what does this modulate?
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found at skeletal neuromuscular junction, adrenal medulla and autonomic ganglia
classified as ligand-gated ion channel receptors the receptor creates a transmembrane ion channel which modulates the flow of ions – primarily Na+ and K+ - in and out of the cell membrane |
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The nicotinic receptor of muscle tissue is a transmembrane glycoprotein consisting of what four types of subunits
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subunits—α, β, γ(orε), and δ.
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Acetylcholine is biosynthesized in cholinergic neurons by what? What is the enzyme catalyzing this reaction? What happens to it?
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by the enzyme-catalyzed transfer of the acetyl group from acetyl coenzyme A (acetyl-S-CoA) to choline, a quaternary ammonium alcohol.
cholineacetyltransferase, is also biosynthesized in the cholinergic neuron. |
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Acetylcholine in the synapse can bind with what? To produce what?
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with cholinergic receptors on the postsynaptic or presynaptic membranes to produce a response.
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What happens to a free acetylcholine that is not bound to a receptor? This hydrolysis is the physiologic mechanism for terminating what?
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is hydrolyzed by acetylcholinesterase (AChE).
for terminating the action of acetylcholine |
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What are 4 Subtypes of Drugs Affecting Cholinergic Neurotransmission?
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Acetylcholine Mimetics: Muscarinic Agonists
Acetylcholinesterase (ACE) Inhibitors: reversible irreversible Acetylcholine Antagonists: Muscarinic Antagonists Nicotinic Antagonists: Neuromuscular Blocking Agents |
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Acetylcholine is the prototypical muscarinic (and nicotinic) agonist, because why?
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it is the physiologic chemical neurotransmitter.
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Acetylcholine is a poor therapeutic agent why?
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because of its lack of nicotinic or muscarinic receptor specificity and because of the chemical and physicochemical properties associated with its ester and quaternary ammonium salt functional groups.
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The SAR for muscarinic agonist activity can be summarized as what?
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The molecule must possess a nitrogen atom capable of bearing a positive charge, preferably a quaternary ammonium salt.
For maximum potency, the size of the alkyl groups substituted on the nitrogen should not exceed the size of a methyl group. The molecule should have an oxygen atom, preferably an ester-like oxygen, capable of participating in a hydrogen bond. There should be a two-carbon unit between the oxygen atom and the nitrogen atom. |