Contacts:
Supervisor(s):
Prof. Lorenzo di Bari, Demartis Salvatore (PPM Services SA, Switzerland)
Title of the PhD project:
Stereochemistry of oligo-based therapeutics
Abstract of the PhD project:
Abstract of the PhD project: Synthetic oligonucleotides, including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are the key tool for the developments of novel therapeutics. The replacement of phosphodiester (PO) with phosphorothioate (PS) linkages is the most extensively used modification, that improves resistance to nucleases and facilitates cellular uptake and bioavailability in vivo. The formal substitution of an oxygen for a sulphur atom in phosphorothioate diesters results in chirality at phosphorous, with either Sp or Rp configuration. This Sp or Rp configuration for each PS linkage couples with the other stereogenic elements of the oligonucleotide chain, leading to the formation of 2n diastereomers, with n being the number of PS linkages present in the PS-modified oligonucleotide. In oligonucleotides containing only a few (1-5) PS linkages, it is well known that Sp and Rp diastereomers have different biological activity. The present project aims to better understand oligo-based therapeutics, by: 1) developing analytical tools for detection and classification of PS stereochemical manifolds; 2) tracing the origins of different manifolds in different batches; 3) developing protocols for separating oligonucleotides populations based on PS stereochemistry; 4) possibly, comparing oligonucleotides with different degree of PS stereocontrol; 5) relating all these features to biological activity in vitro.
Publications:
• Recchimurzo, A. ; Balzano, F., Uccello-Barretta, G., Gherardi, L. Bis-Thiourea Chiral Sensor for the NMR Enantiodiscrimination of N-Acetyl and N-Trifluoroacetyl Amino Acid Derivatives, J. Org. Chem. 2022,87,18,11968-11978.
Oral communications at conferences
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Poster communications at conferences:
• A new chiral solvating agent for the configurational assignment of N-Trifluoroacetyl amino acids derivatives by NMR spectroscopy. CFF2022 Department of Chemistry Pisa
Other achievements:
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