Linkers in Oligonucleotide Conjugates

Direct conjugation of oligonucleotides to ligands such as lipids, peptides, and antibodies is increasingly becoming the dominant delivery strategy in clinical applications. In conjugated oligonucleotides, ligands can be attached covalently via different linkers at various positions, generating a wide range of well-defined conjugated compounds with unique properties. Ligand conjugation can generally occur at the 3'- and 5'-ends on the hydroxyl terminal groups, or at any nucleotides on the 2'-hydoxyl groups and nucleobases (Figure 1)^[1]. The selection of linkers for conjugating ligands to oligonucleotides is crucial in determining the stability of ligand-oligonucleotide conjugates in plasma, as well as their biophysical properties, pharmacokinetic behavior, and therapeutic efficiency. Optimizing the linker structure is a necessary condition for maximizing the activity of conjugated oligonucleotides. Alfa Chemistry has the ability to achieve this optimization.

Figure 1. Ligand conjugation sites in oligonucleotides.

Categories of Linkers

Linkers can broadly be categorized into non-cleavable and cleavable types, with variations in length, polarity, stability, and flexibility. These diverse linkers are used for different types of oligonucleotide conjugates and the choice of linker structure is mostly driven by the desired mode of action. Generally, a non-cleavable linker is preferred when the stability of the conjugate is prioritized over rapid drug release.

Non-cleavable linkers

Non-cleavable linkers are generally more stable, which can avoid the premature release of a drug in circulation. These linkers do not have a particular weak bond in their structure that could be cleaved by enzymes, photo-irradiation, or changes in pH. Commonly used non-cleavable linkers for ligand-oligonucleotide conjugation include amide linkages, triazole linkages, and maleimide linkages.

Cleavable linkers

Cleavable linkers are chemical structures that consist of two functional heads connected by a cleavable bond, which can be cleaved in a controlled fashion to release at least two different molecular species. Cleavable linkers are broadly classified into enzymatic, physicochemical, or chemically labile linkers, determined by the specific conditions required for cleavage. Commonly used cleavable linkers for ligand-oligonucleotide conjugation include disulfide linkages and pH-sensitive linkages.

Figure 2. Commonly used linkers for ligand-oligonucleotide conjugation.

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