Dissertation defence (Chemistry): MSc Lange Yakubu Saleh

MSc Lange Yakubu Saleh defends the dissertation in Chemistry titled “Organomercury oligonucleotides as artificial ribonucleases” at the University of Turku on 10 May 2024 at 12.00 (University of Turku, Main Building, Tauno Nurmela lecture hall, Turku).

The audience can participate in the defence by remote access: https://utu.zoom.us/j/65239858781

Opponent: Professor Roger Strömberg (Karolinska Institutet, Sweden)
Custos: Professor Tuomas Lönnberg (University of Turku)

Doctoral Dissertation at UTUPub: https://urn.fi/URN:ISBN:978-951-29-9665-0


Summary of the Doctoral Dissertation:

Traditional methods to target specific RNA sequences for degradation involve antisense oligonucleotides (ASOs), which have long relied on the natural catalytic activity of RNase H. However, integrating chemical modifications into ASOs for improved cellular delivery and stability has posed significant challenges. Striking the delicate balance between enhancing functionality while preserving RNase H recruitment has proven elusive, hindering optimal therapeutic efficacy.

Artificial Ribonucleases (aRNases) are designed to ively 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 leading aRNases, utilizing metal ions like Cu(II) or Zn(II) in coordination complexes, are prone to dissociation in highly diluted and metal-deficient environments, such as the intracellular medium. However, aRNases with catalytic metal ions bonded to carbon demonstrate resistance to dissociation even under extreme dilution. This suggests a potential to combine the stability of organic compounds with the catalytic effectiveness of metal complexes.

The research commenced with Hg (II), chosen as the catalytic metal ion due to its hydrolytic stability and the ready availability of arylmercury complexes. Kinetic studies conducted across varied pH ranges showed the efficacy of Hg (II) and arylmercury complexes in catalyzing the cleavage of RNA model molecules. Encouraged by these results, two oligonucleotide conjugates, each featuring distinct 5´-terminal organomercury moieties were prepared via either direct mercuration in solution or oximation with an organomercury aldehyde on solid support. Both conjugates exhibited sequence-specific aRNase activity, significantly accelerating reactions compared to catalyst-free conditions and thus paving the way for diverse applications in targeted RNA degradation within cells.
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