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3.2.2.2 Peptide Nucleic Acid (PNA) Encoded Libraries

DOI: 10.1055/sos-SD-241-00212

Farrera-Soler, L.; Vummidi, B. R.; Barluenga, S.; Winssinger, N.Science of Synthesis: DNA-Encoded Libraries, (20241543.

General Introduction

Nucleic acid encoded chemical libraries have emerged as an alternative approach to classical high-throughput screening (HTS) libraries for discovering molecules that bind to protein targets. Library members are individually coupled to unique sequences, serving as amplifiable barcodes that allow for the screening of large compound collections simultaneously. Initially, only single pharmacophores were encoded with nucleic acids; however, soon after that, DNA was used to bring, by virtue of hybridization, two pharmacophores in close proximity.[‌1‌‌3‌] Our group has historically used the power of oligonucleotide hybridization to program the combinatorial assembly of two different fragments onto a DNA template.[‌4‌‌9‌] The use of peptide nucleic acid (PNA) encoded libraries facilitates the synthesis of the library by using solid-phase peptide synthesis (SPPS).[‌10‌,‌11‌] Furthermore, PNA has also been used to constrain peptides into a loop shape that mimics β-turns.[‌12‌‌14‌] We have reported the screening of a new macromolecular structure, termed Dsuprabody (Figure 1), which uses the power of PNA to assemble, encode, and constrain a library of peptide loops that reassemble the peptide loops of the antibody complementarity-determining regions (CDRs).[‌15‌] The screening of a Dsuprabody library has led to the identification of a low-nanomolar binder to PD-L1 and aims to contribute to the discovery of new probes that target large surface interactions, such as protein–protein interactions (PPIs).

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