Spiegelmers

Spiegelmers are mirror-image aptamers composed of the L-enantiomer of nucleotides. Like conventional aptamers, they are short, single-stranded nucleic acids that fold into three-dimensional shapes to bind specific molecular targets with high affinity and selectivity. The defining feature of spiegelmers is their use of the L-form, which makes them resistant to degradation by human nucleases and often gives them improved stability and longer circulating half-lives in vivo.

Spiegelmers are developed through a process called mirror-image SELEX. In this approach, researchers prepare the mirror image of the target protein (the D-enantiomer) and perform iterative binding selections using a library of L-nucleotides. The enriched molecule is an L-aptamer, a spiegelmer, which can then be synthesized chemically. The resulting spiegelmer is designed to bind the natural, biologically relevant form of the target protein, enabling potential therapeutic or diagnostic applications.

Compared with conventional nucleic acid aptamers, spiegelmers offer advantages such as nuclease resistance, reduced immunogenic potential, and favorable pharmacokinetics, facilitating in vivo use. However, the method requires access to the mirror-image form of complex targets, which can complicate discovery for large proteins and glycosylated forms, and development can be costly.

Applications are primarily in therapeutics and diagnostics. A notable example is olaptesed pegol (NOX-A12), a spiegelmer that targets the chemokine CXCL12 to influence tumor biology and other disease processes.