An Amphiphilic Sulfonatocalix[5]arene as an Activator for Membrane Transport of Lysine‐rich Peptides and Proteins

• Published in: Angewandte Chemie International Edition Vol. 60; no. 4; pp. 1875 - 1882
• Main Authors: Pan, Yu‐Chen, Barba‐Bon, Andrea, Tian, Han‐Wen, Ding, Fei, Hennig, Andreas, Nau, Werner M., Guo, Dong‐Sheng
• Format: Journal Article
• Language: English
• Published: Germany 25.01.2021
• Subjects: activators; calixarenes; Calixarenes - chemistry; Cell Membrane - metabolism; lysine; Lysine - metabolism; membrane transport; Membranes, Artificial; molecular recognition; Peptides - metabolism; Protein Transport; Proteins - metabolism; Sulfonic Acids - chemistry; lysine; membrane transport; molecular recognition; calixarenes; activators
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202011185

Lysine (K) is an important target residue for protein and peptide delivery across membranes. K is the most frequently exposed residue in proteins, leading to high demand for the development of K‐compatible transport activators. However, designing activators for K‐rich peptides and proteins is more challenging than for arginine‐rich species because of the kosmotropic nature of K and its recognition difficulty. In this study, we designed a new amphiphilic sulfonatocalix[5]arene (sCx5‐6C) as a K‐compatible transport activator. sCx5‐6C was tailored with two key elements, recognition of K and the ability to embed into membranes. We measured the membrane transport efficiencies of α‐poly‐l‐lysine, heptalysine, and histones across artificial membranes and of α‐poly‐l‐lysine into live cells, activated by sCx5‐6C. The results demonstrate that sCx5‐6C acts as an efficient activator for translocating K‐rich peptides and proteins, which cannot be achieved by known arginine‐compatible activators. An amphiphilic sulfonatocalix[5]arene (sCx5‐6C) was rationally designed as an activator for membrane transport of lysine‐rich peptides and proteins. sCx5‐6C binds tightly with lysine and is able to embed into membranes. The membrane transport efficiencies of α‐poly‐l‐lysine, heptalysine, and histones across artificial membranes and of α‐poly‐l‐lysine into live cells, activated by sCx5‐6C, were measured.