Development of Kilogram-Scale Convergent Liquid-Phase Synthesis of Oligonucleotides.

Oligonucleotide drugs show promise to treat diseases afflicting millions of people. To address the need to manufacture large quantities of oligonucleotide therapeutics, the novel convergent liquid-phase synthesis has been developed for an 18-mer oligonucleotide drug candidate. Fragments containing tetra- and pentamers were synthesized and assembled into the 18-mer without column chromatography, which had a similar impurity profile to material made by standard solid-phase oligonucleotide synthesis.

Solid-Phase Synthesis of Phosphorothioate Oligonucleotides Using Sulfurization Byproducts for in Situ Capping.

Oligonucleotides containing phosphorothioate (PS) linkages have recently demonstrated significant clinical utility. PS oligonucleotides are manufactured via a solid-phase chain elongation process in which a four-reaction cycle consisting of detritylation, coupling, sulfurization, and failure sequence capping with AcO is repeated. In the capping step, uncoupled sequences are acetylated at the 5'-OH to stop the chain growth and control the levels of deletion, or ( n-1), impurities.

Cell penetrating agents based on a polyproline helix scaffold.

Cell penetrating agents were designed and synthesized that introduce cationic and hydrophobic moieties along the backbone of a polyproline helix (PPII) in an amphiphilic manner. The CD profile has the features that are expected for a PPII helix, demonstrating that the addition of these groups had little effect on the backbone structure. Dramatic increases in uptake were found with MCF-7 cells when up to six guanidinium groups were positioned on the polyproline helix, whereas only modest increases in cellular uptake were observed with the amine-containing polyproline compounds as compared to their flexible counterparts.