DNA display of PNA-tagged ligands: a versatile strategy to screen libraries and control geometry of multidentate ligands

Abstract

Over the past decade, several technologies have emerged to access nucleic acid-tagged libraries and select the fittest compound within such libraries. This perspective focuses on recent development with PNA-tagged small molecules displayed on DNA templates for screening purposes and to probe the optimal geometry in multivalent interactions.

Keywords: DNA display; PNA-encoded synthesis; cooperative binding; inhibitor; multivalent interaction; screen.

Figure 1. Synthesis and DNA display of PNA-tagged molecules. (A) Libraries of diverse PNA encoded molecules can be prepared by split and mix synthesis thus facilitating access to large libraries without recourse to complex infrastructure. (B) DNA display offers a simple means to build: (1) assemblies presenting multiple ligand with controlled density (inter-ligand distance) and oligomer order; (2) Organize the ligands on a surface or combinatorially pair ligand on a template. Ligands used in these assemblies can be derived from PNA-encoded synthesis as shown in (A) (a unique color is used for each ligand in (B) to simplify their representation). For the sake of clarity, only one example of each display is shown but other permutations are possible. For examples, it is possible to combinatorially pair ligands using a DNA microarray which includes different ligand pair and different inter-ligand distance or oligomer order.

Figure 2. Selection and amplification of PNA-tagged molecules using DNA display.