Total Synthesis of the TIM-1 IgV Domain via N-to-C Serine/Threonine Ligation Enabled by Knorr Pyrazole Synthesis-Mediated Regeneration of Salicylaldehyde Esters
文献类型：期刊论文
| 作者 | Cheng, Xiaolin1; Sun, Zhenquan1; Wu, Hongxiang1,3; Xiao, Yisa1; Shi, Pengfei1; Li, Can1; Zeng, Jingwen1; Liu, Han1; Li, Xuechen1,2,4 |
| 刊名 | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
 |
| 出版日期 | 2025-12-22 |
| 页码 | 9 |
| ISSN号 | 0002-7863 |
| DOI | 10.1021/jacs.5c17340 |
| 通讯作者 | Li, Xuechen(xuechenl@hku.hk) |
| 英文摘要 | T-cell immunoglobulin and mucin domain-containing protein 1 (TIM-1) have recently emerged as the B-cell immune checkpoint with the potential to overcome the resistance of traditional immune checkpoint blockade therapy. However, the chemical biology of its post-translational glycosylations remains unexplored due to the absence of synthetic access to its homogeneous isoform. Here we report the total synthesis of the TIM-1 IgV-like domain (21-121) through the N-to-C Ser/Thr ligation (STL) with native chemical ligation (NCL). During the synthesis, we uncovered an unprecedented incompatibility of pyruvic acid-mediated salicylaldehyde (SAL) ester regeneration with tryptophan residues. Mechanistic studies revealed that indole side chains condense with pyruvic acid under acidic conditions, leading to side reactions. Guided by this insight, we developed an acetyl acetone (AcAc)-mediated "off-on" method that harnesses Knorr pyrazole synthesis to regenerate SAL esters with exceptional compatibility toward Trp. By combining this advance with aggregation-disrupting strategies, we achieved the first chemical synthesis of the bioactive TIM-1 IgV domain confirmed by various characterizations including high-resolution mass spectroscopy (HRMS), circular dichroism (CD) spectroscopy, and enzyme-linked immunosorbent assay (ELISA). |
| WOS关键词 | ACQUIRED-RESISTANCE ; CHEMICAL-SYNTHESIS ; BLOCKADE ; RECEPTOR ; PEPTIDE ; PROTEIN ; COMPLEX ; GLYCAN |
| 资助项目 | Research Grants Council, University Grants Committee[17303424] ; Innovation and Technology Commission[NA] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001644780900001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/322426]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Li, Xuechen |
| 作者单位 | 1.Univ Hong Kong, Dept Chem, State Key Lab Synthet Chem, Hong Kong 999077, Peoples R China 2.Univ Chinese Acad Sci, Shanghai Inst Organ Chem, Chinese Acad Sci, Shanghai Hong Kong Joint Lab Chem Synth, Shanghai 200032, Peoples R China 3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 4.Ocean Univ China, Qingdao Marine Sci & Technol Ctr, Sch Med & Pharm, Lab Marine Drugs & Bioprod, Qingdao 266237, Peoples R China |
| 推荐引用方式 GB/T 7714 | Cheng, Xiaolin,Sun, Zhenquan,Wu, Hongxiang,et al. Total Synthesis of the TIM-1 IgV Domain via N-to-C Serine/Threonine Ligation Enabled by Knorr Pyrazole Synthesis-Mediated Regeneration of Salicylaldehyde Esters[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2025:9. |
| APA | Cheng, Xiaolin.,Sun, Zhenquan.,Wu, Hongxiang.,Xiao, Yisa.,Shi, Pengfei.,...&Li, Xuechen.(2025).Total Synthesis of the TIM-1 IgV Domain via N-to-C Serine/Threonine Ligation Enabled by Knorr Pyrazole Synthesis-Mediated Regeneration of Salicylaldehyde Esters.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,9. |
| MLA | Cheng, Xiaolin,et al."Total Synthesis of the TIM-1 IgV Domain via N-to-C Serine/Threonine Ligation Enabled by Knorr Pyrazole Synthesis-Mediated Regeneration of Salicylaldehyde Esters".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2025):9. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。