Figure 3.

Structures of common chemical modifications used in nucleic acid therapeutics

(A) First-generation modifications primarily target the phosphate backbone to enhance nuclease resistance. (B) Second-generation modifications focus on the 2′ position of the ribose ring to improve stability and binding affinity. (C) Third-generation modifications involve nucleic acid analogs to further enhance specificity and therapeutic efficacy. Among these analogs, peptide nucleic acids (PNAs) can be modified at the α-, β-, or γ-position with side chains such as cationic quaternary ammonium groups, chiral amino acids, and PEGylated or miniPEG moieties to improve solubility, cellular uptake, and hybridization properties.