Developing New Strategies to Construct Pseudo-natural Macrocycles for Undruggable Targets
文献类型：期刊论文
| 作者 | Wang, Han1,2; Bi, Tongyu1,2; Yang, Weibo1,2 |
| 刊名 | ACCOUNTS OF CHEMICAL RESEARCH
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| 出版日期 | 2025-10-07 |
| 卷号 | 58期号:19页码:3096-3110 |
| ISSN号 | 0001-4842 |
| DOI | 10.1021/acs.accounts.5c00524 |
| 英文摘要 | Up to 85% of human-disease-related target proteins are classified as undruggable. These targets play critical roles in disease pathogenesis and progression yet lack effective agents for therapeutic intervention. In recent years, strategies such as proteolysis-targeting chimeras (PROTACs) and molecular glues have emerged to modulate these undruggable targets, demonstrating considerable promise. Notably, macrocyclic compounds used for molecular glues have exhibited exceptional performance. They comprise ring structures typically formed by 12 or more atoms, representing a unique class of three-dimensional molecular architectures that balance conformational flexibility with structural rigidity. Studies indicate that macrocyclization strategies enhance target selectivity, improve binding affinity, and optimize drug-like characteristics of therapeutic candidates. Despite these advances, current macrocyclic drugs predominantly derive from natural products (NPs). Naturally occurring macrocycles often possess structural complexity, are isolated in low yields, and present significant synthetic challenges, thereby limiting their availability for clinical applications. Consequently, the development of innovative methodologies to construct pseudo-natural macrocycles capable of modulating undruggable targets holds substantial scientific and therapeutic importance-yet remains a formidable challenge. Over the past five years, our group has established a modular biomimetic assembly strategy enabling the rapid generation of diverse pseudo-natural macrocycles exhibiting broad bioactivities. Our macrocycle design principle rests on three key tenets: (I) deconstructing natural product biosynthetic logic into programmable building blocks; (II) developing novel reactions to mimic natural bioactive building blocks; and (III) strategically replacing intricate chiral motifs with readily available amino acid derivatives. This paradigm has facilitated the rapid generation of pseudo-natural macrocycles with significant unexplored biological potential. In this Account, we highlight recent progress made in our group toward development of a modular biomimetic strategy and novel macrocyclization reactions to construct a pseudo-natural macrocycles library for modulating undruggable targets. Specifically, we categorize our work into four parts, including construction of a pseudo-natural macrocycles library, macrocyclic oxime modulating Hemagglutinin (HA) for anti-influenza A H1N1, spiro-fused macrocycles targeting silent information regulator (SIRT3) for treating Parkinson's disease, and macrocycles targeting protein-protein interaction (PPI) for overcoming multidrug resistance (MDR). We highlight that structurally diverse, multifunctional bioactive pseudo-natural macrocycles can be produced concisely and sustainably. We hope that this Account delineated herein will broaden the application of this strategy and inspire the design of a variety of pseudo-natural macrocycles for modulating undruggable targets. We believe that continued efforts based on organic synthesis methodology-driven medicinal chemistry will provide practical solutions to critical challenges in drug discovery. |
| WOS关键词 | P-GLYCOPROTEIN ; DISCOVERY ; CHEMISTRY ; CHAPERONE ; BOND |
| 资助项目 | National Natural Science Foundation of China[82373708] ; National Natural Science Foundation of China[22171275] ; National Natural Science Foundation of China |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001571621500001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321540]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Yang, Weibo |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Han,Bi, Tongyu,Yang, Weibo. Developing New Strategies to Construct Pseudo-natural Macrocycles for Undruggable Targets[J]. ACCOUNTS OF CHEMICAL RESEARCH,2025,58(19):3096-3110. |
| APA | Wang, Han,Bi, Tongyu,&Yang, Weibo.(2025).Developing New Strategies to Construct Pseudo-natural Macrocycles for Undruggable Targets.ACCOUNTS OF CHEMICAL RESEARCH,58(19),3096-3110. |
| MLA | Wang, Han,et al."Developing New Strategies to Construct Pseudo-natural Macrocycles for Undruggable Targets".ACCOUNTS OF CHEMICAL RESEARCH 58.19(2025):3096-3110. |
入库方式： OAI收割
来源：上海药物研究所
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