ADT Exam 1

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Different types of oligonucleotide based therapeutic agents
- tranditional antisense oligonucleotides
- nucleic acid analogs and mimics
- RNAi and siRNA
- Aptamers
Antisense oligonucleotides
- single stranded DNA or RNA that targets mRNA and binds to it complementarly
- 15-20 nucleotides (min of 12-15)
- chemically synthesized
How does binding mRNA by an antisense oligonucleotide lead to inhibition of protein synthesis?
- geometric hinderance
- ribonuclease action
Size of ASONs
- lenght effects specificity of binding
- min of 12-15 nucleotide bases for use in humans
- max of 18 to 24
Advantages of ASONs
- prevent synthesis of harmful proteins
- gene specific
disadvantages of ASONs
- in vivo stability
- drug delivery and cellular uptake
Nucleic acid analogs and mimitecs
- integrate into phosphodiester backbone and prevent protein synthesis
- vitravene for CMV
How do modified ASONs affect the mechanism of action of antisense oligonucleotides?
- modifications increase stability
- decrease degredation
advantages of modified ASONs
- more chemically stable than traditional
- equivalently selective
- less charge so easier to deliver
Disadvantages of modified ASONs

most do not activate RNAase H (do not act catalytically)
RNAi and siRNA

use base pairing to bind mRNA and cleave it before translation into a protein
Problem with RNAi and siRNA

long ds-RNA initiates antiviral response (interferon)
Aptamers
- bind the target protein instead of mRNA
- may bind or have enzymatic activity
- 15-25 bases long
- optimized by invitro selection
4 steps of aptamer syntheses (SELEX)
- pool preparation
- selection of binders
- amplification
- aptamer isolation
Macugen
- aptamer
- anti VEGF
Major problems for delivery of oligonucleotides
- size
- polarity
- cell specificity
Delivery methods
- liposomal
- polumeric
- peptide mediated
- viral

Author

Rx2013

107960

Card Set

ADT Exam 1

Description

Oligonucleotide Based Therapeutics

Updated

2011-10-11T02:55:05Z

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