Citation: Qigui Nie, Shuting Zhong, Yangfeng Li, Gong Zhang, Yizhou Li. Second-generation DNA-encoded multiple display on a constant macrocyclic scaffold enabled by an orthogonal protecting group strategy[J]. Chinese Chemical Letters, ;2022, 33(5): 2559-2563. doi: 10.1016/j.cclet.2021.09.041 shu

Second-generation DNA-encoded multiple display on a constant macrocyclic scaffold enabled by an orthogonal protecting group strategy

Qigui Nie ^a ,
Shuting Zhong ^a ,
Yangfeng Li ^a ,
Gong Zhang ^{a, *,} ,
Yizhou Li ^{a, b, *,}

a.
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China
b.
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 401331, China

gongzhang@cqu.edu.cn

yizhouli@cqu.edu.cn

Received Date: 5 August 2021
Revised Date: 30 August 2021
Accepted Date: 9 September 2021
Available Online: 15 September 2021

Figures(4)

DNA-encoded chemical library (DEL) represents an emerging drug discovery technology to construct compound libraries with abundant chemical combinations. While drug-like small molecule DELs facilitate the discovery of binders against targets with defined pockets, macrocyclic DELs harboring extended scaffolds enable targeting of the protein–protein interaction (PPI) interface. We previously demonstrated the design of the first-generation DNA-encoded multiple display based on a constant macrocyclic scaffold, which harvested binders against difficult targets such as tumor necrosis factor-α (TNF-α). Here, we developed a novel strategy which utilized four orthogonal amine-protecting groups on DNA, to explore larger chemical combinations on the same constant macrocyclic scaffold, following the parallel paradigm to mimic the versatile antibody-like multivalent epitope recognition patterns. We successfully integrated these orthogonal protecting groups with acylation and made a mock second-generation DNA-encoded display combination. This work illustrates a strategy to produce larger encoded multiple display on a constant macrocyclic scaffold, which could facilitate potential binder discovery with enhanced affinity to clinically significant PPI targets.
- DNA-encoded library,
- Macrocyclic scaffold,
- DNA-compatible,
- Protein–protein interaction,
- Chemical probe
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