Significance Drug discovery generally investigates one target at a time, in sharp contrast to living organisms, which mold ligands and targets by evolution of highly complex molecular interaction networks. We recapitulate this modality of discovery by encoding drug structures in DNA, allowing the entire DNA-encoded library to interact with thousands of RNA fold targets, and then decoding both drug and target by sequencing. This information serves as a filter to identify human RNAs aberrantly produced in cancer that are also binding partners of the discovered ligand, leading to a precision medicine candidate that selectively ablates an oncogenic noncoding RNA, reversing a disease-associated phenotype in cells.

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A new methodology to couple peptide fragments on solid support using a traceless isocyanide-based multicomponent reaction is described. The approach uses a microwave-assisted on-resin Ugi four-component reaction to attach a carboxyl free peptide to a supported peptide bearing a free N-terminal amine via the formation of an N-protected amide bond at the ligation site. Afterward, the generated backbone amide protecting group can be efficiently removed by microwave-assisted acidolysis with trifluoroacetic acid to afford a fully deprotected peptide. This straightforward Ugi reaction/deprotection approach was applied to condense various fragment lengths and provided a variety of oligopeptides.

ABSTRACT:A novel dual ring-opening/cleavage strategy to determine the sequence of cyclic peptides from one-bead-onecompound libraries is described. The approach uses a photolabile residue within the macrocycle and as a linker to allow a simultaneous ring-opening and cleavage from the beads upon UV irradiation and provide linearized molecules. Cyclic peptides of 5 to 9 residues were synthesized and the generated linear peptides successfully sequenced by tandem mass spectrometry.Peptide macrocycles are useful tools in chemical biology and medicinal chemistry to study and modulate proteins functions. 1 With great potential as therapeutic agents, they have gained a lot of interest in drug discovery. 2 Compared to their linear counterparts, cyclic peptides are more resistant to proteases and their increased conformational rigidity lowers the entropic cost of binding, making them tighter-binding to a given macromolecule. 3 The great degree of molecular diversity and complexity that can be accessed by simple changes in their sequence has prompted the use of cyclic peptides in combinatorial chemistry. The one-bead-one-compound (OBOC) approach, in which each bead carries many copies of a unique compound, has become a powerful tool in the drug discovery process. 4 However, the use of cyclic peptides in combinatorial OBOC libraries has been limited by difficulties in sequencing hit compounds after the screening. Lacking a free N-terminal amine, Edman degradation sequencing cannot be used on cyclic peptides and complicated fragmentation patterns are obtained by tandem mass spectrometry (MS/MS). 5 In this regard, a one-bead-two-compound approach on topologically segregated bilayer beads has been developed. 6 Initially introduced with an enzymatic shaving strategy 7 and later via chemical approaches, 8 topological bilayer segregation offers the opportunity to synthesize two compounds per bead, namely one which is exposed on the bead surface for screening (cyclic peptide) and the other found inside as a tag for sequencing and compound identification (linear peptide). More recently, Lim and co-workers reported a ring-opening strategy on cyclic peptoids to eliminate the need for encoding. 9 The approach involved the introduction of a cleavable alkylthioaryl bridge in the cycle to allow linearization of the molecule after the screening by thioether oxidation followed by nucleophilic displacement of the sulfone to generate a linear peptoid which can be sequenced by MS/MS. An attractive advantage of the ring-opening strategy over encoding methods is the absence of interference by the coding tag during screening since the same molecules are displayed inside and on the surface of the beads. Based on this strategy, we and other groups placed a methionine or a thioether bridge in cyclic peptides or peptoids and as a linker to allow a simultaneous linearization and compound release from the bead upon treatment with cyanogen bromide. 10 A similar approach was applied to cyclic depsipeptides where an aminolysis with NH 3 or hydrolysi...