Synthesis of next-generation oligonucleotide therapeutics: fine tuning 2' modification to enhance efficacy and cell uptake

The project will involve the synthesis, biophysical analysis and biological evaluation of a new platform for the development of therapeutic oligonucleotides. With these new oligonucleotides available, the project will involve their further development into antibody-oligonucleotide-conjugates. (i) Synthesis of 2' modified nucleoside phosphoramidites (Months 1-12)

(ii) Incorporation of modified phosphoramidites into oligonucleotides by solid phase synthesis (Months 4-15) (iii) Biophysical evaluation of the pairing properties of oligonucleotides incorporating modifications (Months 9-18) (iv) Cellular evaluation of therapeutic oligonucleotides involving targeted siRNA-based knockdown (Months 19-30)

(v) Preparation of modified oligonucleotides bearing reactive groups for the preparation of antibody conjugates (Months 30-36) (vi) Synthesis and characterisation of antibody oligonucleotide conjugates (Months 36-42) (vii) Biological evaluation of antibody oligonucleotide conjugates for the cell delivery of payloads (Months 39-44)

(viii) Writing up (Months 45-48).