反义寡核苷酸 (Antisense Oligonucleotides)

Antisense Oligonucleotides (ASOs) usually refer to short, synthetic, single-stranded DNA or RNA (13-30 nucleotides). Following binding to the targeted mRNA or pre-mRNA, ASOs modulates RNA function by several different mechanisms.

1. ASOs can form an RNA–DNA hybrid that becomes a substrate for RNase H, resulting in target mRNA degradation.

2. ASOs can modulate gene expression via steric block of the ribosomal machinery, which can lead to reduced expression, modulation of splicing and/or restoration of a functional protein.

3. Binding of ASOs to pre-mRNA can alter splicing factor recruitment and regulate splicing events.

The first in vivo applications of ASOs showed limited clinical potential because of the high susceptibility of ASOs with an unmodified phosphoribose backbone to rapid degradation by endonucleases and exonucleases. The modifications in backbone, and sugar molecules give ASOs more affinity and stability. Phosphorodiamidate morpholino oligomers (PMO) are very resistant to nuclease and protease degradation and are mostly used in splicing modulation or translation inhibition. Chemical modifications at 2' position of ribose sugar ring such as 2’-O-methyl (2’-O-me), 2’-Fluoro (2’-F), 2’-O-methoxyethyl (2’-MOE) allow oligonucleotide to adopt RNA like C3’-endo sugar pucker, making it thermally stable.