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SOM 3 > Macromolecules > Flashcards

Macromolecules Flashcards

1
Q

what are the types of RNA therapeutics?

A

Antisense oligonucleotides (ASO’s): inhibit mRNA translation.

RNA interference (RNAi): RNA inhibitors of gene expression by degradation of mRNA.
Forms a RNA –induced silencing complex with a protein ( Argonaute)

Ribozymes: catalytically active RNAs. Cleave covalent bonds in a target RNA.

Aptamers: protein-binding RNAs. Length of RNA that binds to a protein (like a small molecule inhibitor)

RNA vaccines: introduces mRNA sequence coded for a disease specific antigen into cells to build up an immune response

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2
Q

what are Antisense Oligonucleotides (ASOs)?

A

short strand
Entry of this RNA into the cell can lead to target protein knockdown in the cytoplasm or the nucleus:

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3
Q

what happens when ASOs bind in the cytoplasm?

A

bind to mRNA

– triggers ribonuclease (RNase H) activity OR
– inhibits ribosomal mRNA translation by steric hindrance.

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4
Q

what happens when ASOs bind in the nucleus?

A

regulates mRNA maturation

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5
Q

how do ASOs regulate mRNA maturation?

A

– inhibition of 5’ cap being formed OR
– inhibition of RNA splicing OR
– recruits ribonuclease (RNase H)

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6
Q

what are some examples of RNA interference?

A

siRNA
RNAi

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7
Q

whats the difference between ASO’s and RNAi?

A
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8
Q

what are RNA interferences?

A
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9
Q

how do ribozymes work?

A

cleave mRNA molecules next to a recognition sequence = destroying RNA sequences

similar to protein nucleases

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10
Q

how do aptamers work?

A

aptamer sequence = functional aptamer = target binding = preventing functionality of bound molecule

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11
Q

half life of RNA

A

short half life = fast degradation

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12
Q

when may RNA vaccines not be safe to administer?

A

for patients susceptible to autoimmune response

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13
Q

LOOK AT NOTES FOR DESIGNING OLIGONUCLEOTIDES

A
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14
Q

what is the disadvantage of RNA therapeutics?

A
  1. enzyme degradation - activity of ribonuclease
  2. fast excretion - unmodified oligonucleotides have a poor PK due to weak plasma binding = filtration thru the kidney
  3. poor absorption/bioavailability= poor cellular uptake
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15
Q

what can chemical modifications do to oligonucleotides?

A

stabilise ASOs and resistant to ribonucleases = increase half life
retain/improve RNAse H efficacy
reduce immunogenicity
increase affinity and potency
decrease non-sequence specific toxicity

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16
Q

how do you prevent ribonuclease attacking RNA therapeutics?

A

chemically modify the antisense oligonucleotide

17
Q

what are generation one modified antisense oligonucleotides?

A

phosphorothioate (PS) modifications to the backbone

18
Q

what are generation two modified antisense oligonucleotides?

A

changes to the 2’ position of the sugar

2’-MOE, 2’-O-methyl (2’OMe) , 2’-fluoro

19
Q

what are generation three modified antisense oligonucleotides?

A

ASOs with modifications in the sugar region with a non-charged backbone

Peptide Nucleic Acid (PNA)
Locked nucleic acid (LNA)

20
Q

what are the advantages/disadvantages of PS-modifications?

A

adv
- increase nuclease-resistance
- increase bioavailability

disadv
- reduces binding affinity
- non-specific interactions with cell surface and other proteins

21
Q

what are the advantages/disadvantages of 2’-MOE, 2’-O-methyl (2’OMe) , 2’-fluoro -modifications?

A

adv
- increase nuclease-resistance
- tight binding between ASO and RNA

disadv
reduced RNase H activity

22
Q

how do you overcome the disadvantages of using generation 2
modified antisense oligonucleotides?

A

reduced RNase H activity - disadvantage

overcome by using in combination with generation 1 modified antisense oligonucleotides

23
Q

what are the advantages/disadvantages of Peptide Nucleic Acid (PNA)?

A

adv
- high binding affinity to RNA/DNA than RNA-RNA and DNA-DNA
- stable towards nucleases and peptidases
- bind double-stranded DNA = transcriptional arrest

disadv
- effects produced by steric inhibition of mRNA translation

24
Q

what are the advantages/disadvantages of Locked Nucleic Acid (LNA)?

A

adv
- increased binding affinity towards target mRNA
- resistance to nuclease degradation

disadv
- not processed by RNase H

25
Q

what are the PK of antisense oligonucleotides?

A
  1. uncharged oligonucleotides such as PNA and morpholino = low plasma protein binding = rapidly cleared
  2. single stranded, PS-modified ASOs = high affinity for plasma protein = decrease excretion
  3. ASO bind to plasma protein = decrease excretion
26
Q

SPINRAZA CASE STUDY LOOK OVER NOTES

A

SOM 3 (26 decks)

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