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Review
. 2024 Feb;14(2):492-516.
doi: 10.1016/j.apsb.2023.10.001. Epub 2023 Oct 11.

Evolution of chemistry and selection technology for DNA-encoded library

Peixiang Ma  1 , Shuning Zhang  1   2 , Qianping Huang  2 , Yuang Gu  2 , Zhi Zhou  3 , Wei Hou  4 , Wei Yi  3 , Hongtao Xu  2
Affiliations
Review

Evolution of chemistry and selection technology for DNA-encoded library

Peixiang Ma et al. Acta Pharm Sin B. 2024 Feb.

Abstract

DNA-encoded chemical library (DEL) links the power of amplifiable genetics and the non-self-replicating chemical phenotypes, generating a diverse chemical world. In analogy with the biological world, the DEL world can evolve by using a chemical central dogma, wherein DNA replicates using the PCR reactions to amplify the genetic codes, DNA sequencing transcripts the genetic information, and DNA-compatible synthesis translates into chemical phenotypes. Importantly, DNA-compatible synthesis is the key to expanding the DEL chemical space. Besides, the evolution-driven selection system pushes the chemicals to evolve under the selective pressure, i.e., desired selection strategies. In this perspective, we summarized recent advances in expanding DEL synthetic toolbox and panning strategies, which will shed light on the drug discovery harnessing in vitro evolution of chemicals via DEL.

Keywords: Chemical central dogma; DNA-compatible synthesis; DNA-encoded library; Drug discovery; High-throughput selection; In vitro evolution.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Image 1
Graphical abstract
Figure 1
Figure 1
Overview of DNA-encoded library (DEL) technology. (a) Central dogma in biology. (b) Chemical central dogma in DEL. (c) Central dogma in biology vs. chemical central dogma in DEL.
Figure 2
Figure 2
DEL synthesis, selection, and formats. (a) “Split & Pool” DEL synthesis and affinity-based DEL selection. (b) Format of DELs.
Figure 3
Figure 3
Representative conventional DEL chemistry. (a) Amine capping reactions. (b) CuAAC. (c) Metal-mediated cross-coupling reactions. (d) On-DNA heterocycle synthesis.
Figure 4
Figure 4
Photoinduced azide-reduction and Giese addition. (a) Photoinduced selective azide-reduction. (b) Photoinduced decarboxylation Giese addition. (c) Photoinduced Giese addition from alkyl halide. (d) Photoinduced Giese addition from the diazo compound.
Figure 5
Figure 5
Photoinduced defluorinative alkylation and hydroalkylation of DNA-conjugated CF3‒alkenes. (a) Photoinduced defluorinative alkylation. (b) Photoinduced hydroalkylation of DNA-conjugated CF3‒alkenes via EDA complex.
Figure 6
Figure 6
Photoredox promoted C(sp2)‒C(sp3) and C(sp2)‒C(sp2) cross-coupling. (a) Photoredox catalyzed C(sp2)‒C(sp3) cross-coupling. (b) Photoredox catalyzed C(sp2)‒C(sp2) cross-coupling via C–H arylation of heteroarenes.
Figure 7
Figure 7
Photoinduced cycloaddition reaction. (a) Photoinduced [2 + 2] cycloaddition. (b) Photoinduced [2 + 1] cycloaddition.
Figure 8
Figure 8
DNA-compatible C(sp2)‒H activation. (a) C–H olefination. (b) C–H selenylation. (c) C–H activation/[4 + 2] annulation. (d) C–H activation/[4 + 3] annulation.
Figure 9
Figure 9
DNA-compatible C(sp3)‒H functionalization. (a) C(sp3)‒H arylation. (b) Photoinduced cross-dehydrogenative coupling.
Figure 10
Figure 10
DNA-compatible C(3)‒H selenylation of indole. (a) Click selenylation with BSEA. (b) Click selenylation with BTSA. (c) Other methods.
Figure 11
Figure 11
Graphic description of micellar-mediated reactions. (a) On-DNA micellar catalysis―partition DNA from the acidic or severe reaction condition. (b) Block copolymer with “SO3H” in the hydrophobic core. (c) Block copolymer with “SO3H” in a hydrophilic shell. (d) Block copolymer without the “SO3H” group. (e) Block copolymer with “bipyridine” in the hydrophobic core.
Figure 12
Figure 12
Micellar-mediated reactions. (a) Povarov reaction. (b) Gröbke–Blackburn–Bienaymé reaction. (c) Oxidation of DNA-alcohol to aldehyde. (d) Suzuki–Miyaura coupling.
Figure 13
Figure 13
RASS-enabled reactivity expanding. (a) Principle and workflow of RASS. (b) Decarboxylative C(sp2)‒C(sp3) coupling. (c) Electrochemical amination. (d) Reductive amination. (e) A three-cycle DEL rehearsal.
Figure 14
Figure 14
RASS-enabled S/P–C and S–N bond formation reactions. (a) C(sp2)‒S and C(sp2)‒P coupling. (b) C(sp3)‒SO2 and/or SO2–N formation reaction.
Figure 15
Figure 15
APTAC-enabled transformations. (a) Umpolung addition. (b) The Sn amine protocol (SnAP).
Figure 16
Figure 16
Substate activation strategy-enabled transformations. (a) Strain-promoted cycloaddition. (b) Arylation of weak nucleophiles via umpolung and synthetic utility.
Figure 17
Figure 17
Affinity-based selections against targets on solid phase. (a) Solid phase DEL selection. (b) Online chromatography DEL selection. (c) Live cell surface DEL selection.
Figure 18
Figure 18
Affinity-based selections against targets in solution. (a) Photo-cross-linker-based in solution DEL selection. (b) “Ligate-crosslink-purify”-based DEL selection. (c) Fusion enzyme-based DEL selection.
Figure 19
Figure 19
Sequence integration-based DEL selections. (a) Interaction-dependent PCR (ODPCR)-based DEL selection. (b) Ligand-target pairs-based DEL selection.
See this image and copyright information in PMC

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