与核酸兼容的化学反应开发进展

刘子健; 穆柏杨; 段志强; 王璇; 陆晓杰

doi:10.12211/2096-8280.2024-008

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与核酸兼容的化学反应开发进展

特约评述 | 更新时间：2025-03-19

- 与核酸兼容的化学反应开发进展
- Advances in the development of DNA-compatible chemistries
- 合成生物学 2024年5卷第5期页码：1102-1124
- 作者机构：
  
  1.中国科学院上海药物研究所，原创新药研究全国重点实验室，上海 201203
  2.中国科学院大学，北京 100049
  3.山东第二医科大学，山东潍坊 261053
- 作者简介：
  
  [ "刘子健（2000—），男，硕士研究生。研究方向为on-DNA化学反应开发和DNA编码化合物库的构建和筛选。 E-mail：liuzijian@simm.ac.cn" ]
  [ "穆柏杨（2000—），男，硕士研究生。研究方向为on-DNA化学反应开发和苗头化合物发现和优化。 E-mail：mubaiyang@simm.ac.cn" ]
  [ "陆晓杰（1983—），男，博士，研究员，博士生导师。研究方向为DNA编码化合库技术的开发和应用。 E-mail：xjlu@simm.ac.cn" ]
- 基金信息：
  
  国家自然科学基金(22377139);国家重点研发计划(91953203)
- DOI：10.12211/2096-8280.2024-008
  中图分类号： R914.2;Q81
- 收稿：2024-01-17，
  
  修回：2024-05-30，
  
  纸质出版：2024-10-31
- 稿件说明：
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刘子健，穆柏杨，段志强，王璇，陆晓杰. 与核酸兼容的化学反应开发进展［J］. 合成生物学， 2024， 5（5）： 1102-1124

LIU Zijian， MU Baiyang， DUAN Zhiqiang， WANG Xuan， LU Xiaojie. Advances in the development of DNA-compatible chemistries［J］. Synthetic Biology Journal， 2024， 5（5）： 1102-1124
刘子健，穆柏杨，段志强，王璇，陆晓杰. 与核酸兼容的化学反应开发进展［J］. 合成生物学， 2024， 5（5）： 1102-1124 DOI： 10.12211/2096-8280.2024-008.

LIU Zijian， MU Baiyang， DUAN Zhiqiang， WANG Xuan， LU Xiaojie. Advances in the development of DNA-compatible chemistries［J］. Synthetic Biology Journal， 2024， 5（5）： 1102-1124 DOI： 10.12211/2096-8280.2024-008.

摘要

DNA编码化合物库（DNA-Encoded Library

，DEL）技术作为一种新兴的小分子药物筛选手段已经成为新药研发中不可或缺的重要技术平台。与核酸兼容（on-DNA）的化学反应对于构建具有丰富化学空间和结构多样性的DEL具有重要意义。近年来，on-DNA化学反应的数量不断增加，极大地拓宽了可用于DEL构建的化学反应范畴。同时，一系列创新性的反应方法，诸如光催化、固相合成以及生物合成等，亦在on-DNA化学反应领域不断涌现，进一步推动了该领域的发展。本文系统综述了近年来金属催化的on-DNA化学反应，包括：C（sp

）—C（sp

）键生成反应、C（sp

）—C（sp

）键生成反应、C（sp

）—C（sp

）键生成反应以及C（sp

）—X键生成反应；采用目标导向合成策略和多样性导向合成策略合成具有单环、稠环、螺环等on-DNA优势骨架；光催化和酶催化on-DNA化学反应等的研究进展。然而，目前开发的on-DNA化学反应仍然存在诸如与核酸的兼容性、底物适用性等问题，开发更高效、更稳定且能在温和条件下进行的on-DNA化学反应，发展新型的on-DNA化学反应类型，以及结合高通量筛选和计算机辅助的on-DNA反应开发仍然具有重要意义。

Abstract

DNA-Encoded Library (DEL) technology

as an emerging means of small molecule drug screening

has become an important and indispensable technology platform for new drug discovery and development. The technology incorporates many advantages from combinatorial chemistry

molecular biology

and chemical bioinformatics

which greatly improve the efficiency of compound library synthesis and screening. Meanwhile

driven by the development of nucleic acid-compatible chemical reactions and high-throughput sequencing technology

DEL technology has made remarkable progress and gradually become a fast

economical

and efficient high-throughput screening platform

and has been more and more widely used in seedling compounds screening by universities

research institutes

and large pharmaceutical companies. The success of a DEL screening relies heavily on the chemical space and structural diversity of the compound libraries

both of which are directly affected by the number of chemical reactions compatible with nucleic acids. Therefore

developing the on-DNA chemical reactions to continuously enrich the chemical toolbox for DEL synthesis and thus enhance the structural diversity and drug potential of the molecules in the libraries has been the focus in this field. In recent years

the number of on-DNA chemical reactions has increased significantly

greatly broadening the scope of chemical reac

tions available for DEL construction. Meanwhile

a series of novel reaction methods

such as photocatalysis

electrocatalysis

and biosynthesis

have also emerged in the application of on-DNA chemical reactions and further expanded the field that on-DNA chemical reactions can reach. In this paper

we systematically review the metal-catalyzed on-DNA chemical reactions in recent years

including C(sp

)—C(sp

) bond-formation reactions

C(sp

)—C(sp

) bond-formation reactions

C(sp

)—C(sp

) bond-formation reactions

and C(sp

)—X bond-formation reactions; the synthesis of on-DNA privileged heterocycles with single-ring

fused-ring

and spirocyclic rings by using target-oriented synthetic and diversity-oriented synthetic strategies; the research progress of photocatalytic and enzyme-catalyzed on-DNA chemical reactions. However

the current developments in on-DNA reactions also have limitations

such as compatibility with nucleic acids and substrate suitability. In the future

it is important to exploit more robust on-DNA reactions that can proceed under mild conditions

new types of on-DNA reactions

and the combination of high-throughput screening and computer-assisted on-DNA reactions.

关键词

Keywords

references

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