Antisense oligonucleotides (ASOs) leverage the natural catalytic activity of RNases H to target specific RNA sequences for degradation. However, the challenge lies in incorporating chemical modifications into ASOs to enhance cellular delivery, stability and binding affinity without compromising their ability to recruit RNases H. This delicate balance often poses limitations in achieving optimal therapeutic outcomes. Artificial ribonucleases (aRNases) are designed to selectively cleave RNA sequences, mirroring the function of natural ribonucleases but tailored for specific applications. These synthetic counterparts effectively cleave phosphodiester bonds in RNA molecules, enabling diverse applications, including targeted degradation of specific RNA sequences within cells.

The current state-of-the-art aRNases that rely on metal ions, such as Cu(II) or Zn(II) in coordination complexes, face challenges in highly diluted and metaldeficient conditions, such as those found in the intracellular medium. aRNases having the catalytic metal ions bonded to carbon resist dissociation even at extreme dilution, thus promising to combine the stability of organic compounds with the catalytic efficacy of metal complexes. We chose Hg(II) as the catalytic metal ion for the hydrolytic stability, and ready availability of arylmercury complexes.

This thesis presents kinetic studies conducted across various pH ranges on the cleavage of RNA model molecule adenylyl-3´,5´-(2´,3´-O-methyleneadenosine) catalyzed by mercury (II) and an arylmercury complex. Both agents facilitated the cleavage of the RNA model compound. Additionally, two oligonucleotide conjugates, featuring the same sequence but differing in the 5′-terminal organomercury moiety, were synthesized using established methods. One was synthesized through direct mercuration in solution, while the other was produced via oximation with an organomercury aldehyde on a solid support. These two oligonucleotide conjugates functioned as sequence-specific aRNases. The reactions conducted in the presence of mercury (II), an arylmercury complex, or the two organomercurated aRNases, exhibited considerable rate accelerations compared to reactions in the absence of any catalyst.