Opportunities for Expanding Encoded Chemical Diversification and Improving Hit Enrichment in mRNA‐Displayed Peptide Libraries

Abstract

DNA‐encoded small‐molecule libraries and mRNA displayed peptide libraries both use numerically large pools of oligonucleotide‐tagged molecules to identify potential hits for protein targets. They differ dramatically, however, in the ‘drug‐likeness’ of the molecules that each can be used to discover. We give here an overview of the two techniques, comparing some advantages and disadvantages of each, and suggest areas where particularly mRNA display can benefit from adopting advances developed with DNA‐encoded small molecule libraries. We outline cases where chemical modification of the peptide library has already been used in mRNA display, and survey opportunities to expand this using examples from DNA‐encoded small molecule libraries. We also propose potential opportunities for encoding such reactions within the mRNA/cDNA tag of an mRNA‐displayed peptide library to allow a more diversity‐oriented approach to library modification. Finally, we outline alternate approaches for enriching target‐binding hits from a pooled and tagged library, and close by detailing several examples of how an adjusted mRNA‐display based approach could be used to discover new ‘drug‐like’ modified small peptides.

Chemical Stability of mRNA/cDNA Complexes: Defining the Limits of mRNA display

“…[14,17] By contrast, the compatible reaction space is much less extensively explored for mRNA display. We believe that there is a great potential for many of these reactions to be accessible with mRNA display, given their compatibility with DNA in DEL, [18] but the presence of RNA may also lead to meaningful differences in stability.…”