Synthetic oligonucleotides constitute an important class of therapeutics being developed to treat a variety of indications, including neurodegenerative diseases, ophthalmic, cancer, respiratory disorders, and viral infections. Despite the promising results of oligonucleotides as therapeutic agents, many challenges still need to be addressed for their widespread use in clinical applications. Poor cellular uptake and pharmacokinetic properties hinder positive clinical outcomes (and overcoming regulatory hurdles). To improve these properties, chemical modification of ASO, siRNA, CpG, miRNA, and aptamer oligonucleotides has attracted great interest in drug development. In particular, covalent attachment to peptides (i.e., peptide-oligonucleotide conjugates, POCs) has improved cellular uptake (including into the cell nucleus), cell-specific delivery, tissue targeting, and intracellular distribution.

We are experts in the synthesis of complex New Chemical Entities with the capacity to produce from milligram to multi-kg batches of GMP and non-GMP peptides and oligonucleotides.

A parallel synthetic approach provides a wide range of conjugation methods and attachment sites for assembling peptide-oligonucleotide conjugates, including amide bonds, disulfide, and thioether linkages, and triazole (i.e., Click Chemistry), which are among the most important in POC therapeutic development. Most often, peptides are conjugated to oligonucleotides at the 5′- or 3’-ends and less commonly to the internal bases and 2′-position of the ribose sugar. For conjugation at the 5’-end, linker phosphoramidites are incorporated using standard solid-phase phosphoramidite oligonucleotide synthesis during the activation and coupling steps. Various 5′ (and 3′) modifiers are available as derivatized nucleoside phosphoramidites, including thiol-based derivatives, alkyne moieties, and amine groups.