A DNA‐Encoded Chemical Library Based on Peptide Macrocycles

Abstract

The synthesis and characterization of an ovel DNA-encodedl ibraryo fm acrocyclic peptided erivatives are described;t he macrocyclesa re based on three sets of proteinogenic and non-proteinogenic amino acid building blocks and featuring the use of copper(I)-catalyzeda lkyneazide cycloaddition (CuAAC) reactionf or ring closure. The library (termedY O-DEL) whichc ontains1254 838 compounds, was encoded with DNA in single-stranded format andw as screened against target proteins of interest using affinity capturep rocedures and photocrosslinking. YO-DEL selections yieldeds pecific binders against serum albumins, carbonic anhydrases and NKp46, am arker of activated Natural Killer cells.

Recent Advances on the Selection Methods of DNA‐Encoded Libraries

“…Although similar results were observed, the photocrosslinking method identified additional SAR features in the selection fingerprints. [71] In addition, similar affinity enhancement has also been observed with reversible, noncovalent "crosslinkers". [65b,72]…”

Macrocyclization strategies for cyclic peptides and peptidomimetics

“…264 When a short spacer on the C-terminus is desired for headto-tail cyclization, it is possible to introduce a C-terminal propargylamine by using a silyl-based alkyne modifying (SAM)-resin. 272,273 CuAAC does not require protecting groups and can be performed on-resin 267,271,[274][275][276][277][278] as well as in solution, 262,[265][266][267][268][269][279][280][281][282][283][284][285][286][287][288][289][290][291][292][293][294][295] which is more common and proceeds under mild conditions. Cu salts most frequently used are CuSO 4 with sodium ascorbate, or Cu I salts such as CuI and…”

“…286 Finally, the reaction was also used successfully in the synthesis of a DNA-encoded peptidomimetic library with 10 6 members to identify ligands against several targets with K D s in the μM range. 291 Showcasing the versatility of having a set of chemoselective reactions, several efforts have successfully obtained multicyclic peptides by combining different cyclisation strategies, such as CuAAC, enzymatically-mediated lactamization, oxime ligations, or thioether formation on scaffolds, yielding structurally unique moieties. [305][306][307] 10.2 1,5-Disubstituted 1,2,3-triazole formation: rutheniumcatalyzed azide-alkyne cycloaddition A 1,5-disubstiuted 1,2,3-triazole is similar to an E-amide bond in terms of H-bond acceptor and donor positions and can function as a bioisostere for it.…”

Macrocyclic DNA-encoded chemical libraries: a historical perspective

“…38,39 Since then several academic and industrial researchers published diverse DELs and methods for their synthesis. [38][39][40][41][42][43][44] Also, DNA-encoded peptidomimetic libraries were created and successfully screened. 41,45 In this review, we will describe the historical course of DNA-encoded libraries of macrocycles empowered by DNA-templated and, more recently, DNA-recorded synthesis.…”

“…The Neri/Scheuermann lab constructed a MP-DEL with three variable positions using sets of natural and unnatural amino acids. 44 Cyclization was achieved through CuAAC, with a collection of bifunctional carboxylic acid-alkynes. The obtained 1.3 Mio compounds were encoded by single-stranded DNA, allowing for both the screening of proteins of interest by classic affinity capture procedures, and by photo-crosslinking.…”