nucleic acid based therapeutics (luke) - 1151

general function of nucleic acids

DNA is permanent genetic material, transcribed into mRNA

mRNA is then transLATED into proteins

mRNA acts as both a TARGET and an active drug

nucleotide of DNA

nitrogenous base, sugar (deoxyribose) and phosphate group

nucleoside

nitrogenous base and sugar (deoxyribose)

nitrogenous base

contains the functional groups, and undergoes acid-base reactions to be in the protonated form

sugars

deoxyribose for DNA (lacking 2’ hydroxyl group)

ribose for RNA

phosphate chain

acts as the backbone, connected via phosphodiester bonds

phosphodiester bonds

a detached nucleotide has a chain of 3 phosphates, but a diphosphate detaches when the phosphodiester bond is formed

chain of DNA

made of nucleotides > nitrogenous base/sugar/phosphate

phosphate backbone

5’ end has a phosphate, 3’ end has a hydroxyl group

antiparallel and double stranded > twists to form the double helix with minor and major grooves

antiparallel

complimentary strands that run in opposite directions

RNA (differences from DNA)

has ribose sugar > that has an extra hydroxyl group on 2’ position

is single stranded

uracil replaces thymine (now its U and A rather than T/A)

Antisense oligonucleotides (ASOs)

SINGLE stranded

DNA

ACTION: binds to complimentary RNA strands to alter translation > can stop synthesis of protein OR trigger RNA splicing to form missing mRNA that codes for unproduced proteins

TARGETS: an alternative gene (to an inefficient/abnormal one) that can be spliced to encode for missing protein

siRNA (short interfering RNA)

DOUBLE stranded

RNA

PRE: the strands separate once reaching target, the active strand (that is complementary to target strand) enters the cell > binding to target mRNA

ACTION: (once bound) breaks down the mRNA > leading to complete gene silencing

TARGETS: defective gene that produce abnormal proteins (that have harmful effects)

Aptamers

SINGLE stranded > but they FOLD INTO COMPLEX

DNA or RNA

ACTION: similar to antibodies MUCH SMALLER > can specifically bind to protein/receptor/enzyme/etc ALSO binds via intermolecular forces (h-bonding, dipole-dipole, dispersion)

NOTE: can force induced fix (like a ligand to an enzyme) AND has ‘off switch’ > introduce a complimentary strand and this will denature the complex of the aptamer

CRISPR