Synthesis and Exon-Skipping Properties of a 3′-Ursodeoxycholic Acid-Conjugated Oligonucleotide Targeting DMD Pre-mRNA: Pre-Synthetic versus Post-Synthetic Approach

Elena Marchesi (1) , Matteo Bovolenta (1) , Lorenzo Preti (1) , Massimo L Capobianco (2) , Kamel Mamchaoui (3) , Monica Bertoldo (1, 2) , Daniela Perrone (1)

1 UniFE - Università degli Studi di Ferrara = University of Ferrara
2 Italian Research National Council
3 Centre de recherche en Myologie – U974 SU-INSERM

Steric blocking antisense oligonucleotides (ASO) are promising tools for splice modulation such as exon-skipping, although their therapeutic effect may be compromised by insufficient delivery. To address this issue, we investigated the synthesis of a 20-mer 2′-OMe PS oligonucleotide conjugated at 3′-end with ursodeoxycholic acid (UDCA) involved in the targeting of human DMD exon 51, by exploiting both a pre-synthetic and a solution phase approach. The two approaches have been compared. Both strategies successfully provided the desired ASO 51 3′-UDC in good yield and purity. It should be pointed out that the pre-synthetic approach insured better yields and proved to be more cost-effective. The exon skipping efficiency of the conjugated oligonucleotide was evaluated in myogenic cell lines and compared to that of unconjugated one: a better performance was determined for ASO 51 3′-UDC with an average 9.5-fold increase with respect to ASO 51.

Mots clés: antisense oligonucleotide; conjugation; bile acid; ursodeoxycholic acid; solid support; solid phase synthesis; exon-skipping; dystrophin

Domaines: Sciences du Vivant [q-bio]

Elena Marchesi, Matteo Bovolenta, Lorenzo Preti, Massimo L Capobianco, Kamel Mamchaoui, et al.. Synthesis and Exon-Skipping Properties of a 3′-Ursodeoxycholic Acid-Conjugated Oligonucleotide Targeting DMD Pre-mRNA: Pre-Synthetic versus Post-Synthetic Approach. Molecules, 2021, 26 (24), pp.7662. ⟨10.3390/molecules26247662⟩. ⟨hal-03510261⟩