chapter  15
28 Pages

Utilizing Chemistry to Harness RNA Interference Pathways for Therapeutics: Chemically Modified siRNAs and Antagomirs

WithMuthiah Manoharan, Kallanthottathil G. Rajeev

Small molecule pharmaceutical drugs meet the “Lipinski Rules,” which state that drugs with favorable absorption, distribution, metabolism, and elimination (ADME) properties have certain physical characteristics, including a high lipophilicity, presence of not more than five hydrogen bond

donors and ten hydrogen bond acceptors, and molecular weight not more than 500. In sharp contrast, short interfering RNAs (siRNAs) lack these drug-like properties due to their large size (two turns of a nucleic acid double helix), nearly 40 anionic charges (due to the phosphodiester backbone), and high-molecular-weight (over 13 kDa). In aqueous solution, with their sugar-phosphate backbone exposed to water, siRNAs are extremely hydrophilic and heavily hydrated. Furthermore, siRNAs are very unstable in serum due to susceptibility to degradation by serum nucleases, contributing to their short half-life in vivo.