Year: 2025
Type: article
Abstract: For peptide-drug conjugate (PDC) development, high-quality peptide ligands with easy functionalization are essential. Combinatorial chemical peptide libraries are key for discovering high-affinity non-natural ligands, yet their utility has long been hindered by low-purity libraries that cause false positives. To address this, we developed an N-terminal cysteine-based dynamic catch-and-release (CbDCR) platform, leveraging its unique 1,2-aminothiol motif as a privileged handle for site-selective orthogonal conjugation, enabling efficient library purification while retaining a universal anchor for downstream functionalization. A recyclable 2-formylphenylboronic acid resin (2FPBA resin) was designed to catch and release N-terminal cysteine-containing peptides in a pH-responsive manner, eliminating the need for complex tags and providing simplicity, scalability, and high purification efficiency through optimized workflows. The platform effectively purifies SPPS-synthesized peptides, enriches N-terminal cysteine-containing peptides from protein lysates, supports high-purity split-and-pool library preparation, and integrates with microplate-based high-throughput workflows. Using a highly pure "RGD"-focused nonstandard library, high-affinity integrin αvβ6-targeting peptides were identified, and three peptide-radionuclide conjugates with potential diagnostic value for pancreatic cancer were constructed via N-terminal cysteine. Overall, CbDCR streamlines library purification, affinity screening, and conjugate construction, accelerating the development of high-value peptide ligands and PDCs.
Source: JACS Au
Authors: Quan Zuo, Jie Yan, Hongyi Huang, Quanshu He, Ximiao Yang, Hao Tian, Zihan Huang, Junlong Lu, Guoqing Li, Zirui Zhang, Minzi Lu, Rui Wang, Kuan Hu
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,500
Funders: National Natural Science Foundation of China, China Postdoctoral Science Foundation, Chinese Academy of Medical Sciences, Soochow University, Peking Union Medical College, China National Nuclear Corporation, Beijing Municipal Natural Science Foundation, Beijing Nova Program, Fundamental Research Funds for the Central Universities
Awards: G1014599262, G1863677309, G1882610547, G2366086704, G2381989466, G2399492439, G2730892855, G2980200672, G3503529834, G4195902096, G4212779839, G4498298630, G4521889413, G4746481246, G4969500791, 基于罕见瘤种患者来源的类器官模型与药物筛选, G5048835152, G5437540921, G5634768449, G5830508426, G6195305767, G6425160497, G6573652539, G7176071266, G7282893586, G7693631591, G7950614297, G8223270555, G856769776, G885406935
OpenAlex ID: W4417436875