Cyclic peptide facial amphiphile preprogrammed to self-assemble into bioactive peptide capsules.

Self-assembled peptide nanostructures have shown great potential as promising biomaterials. Peptides have the advantage of being intrinsically biocompatible materials. Peptides, as self-assembling building blocks, have mostly been designed to have head/tail molecular configuration. Since there is a great deal of interest in the precise control of a self-assembly process, novel building blocks significantly different from those with conventional head/tail configuration might provide ample opportunities for constructing elaborate, versatile, and smart nanostructures. Cyclic peptides, due to their constrained nature, are one of those self-assembly building blocks that have unique topological features compared with conventional linear (head/tail) peptides. Another important self-assembling building block that has a special architecture is the facial amphiphiles. In facial amphiphiles, the hydrophilic and -phobic groups are located on two opposite faces, rather than at two ends as in head/tail amphiphiles. Herein, we present an approach to construct a novel type of self-assembling building blocks in which the characteristics of cyclic peptides and facial amphiphiles are combined. The self-assembly behavior of this novel cyclic peptide facial amphiphile (CPFA) could be regulated through the judicious design of molecular structure, showing the power of this rational approach for precise nanostructural control. Capsules or vesicles are one of the most important nanostructural morphologies that can be utilized in many types of bioapplications, including drug, gene, and protein delivery. Capsules have hollow interior within which cargo molecules can be entrapped. Upon suitable functionalization of outer shell, capsules can be made to bind or enter the cells. Traditionally, self-assembled capsules have been fabricated by using amphiphilic molecules of head/tail configuration, such as amphiphilic lipids and block copolymers. The supramolecular morphology of the head/tail amphiphiles depends highly on the relative volume fraction between hydrophilic and -phobic blocks. Therefore, the capsule formation, in most cases, can be possible only by adjusting the volume fraction by trial and error. To devise a building block preprogrammed to have a predictable self-assembly property for capsule formation, a symmetrical CPFA with a C3-symmetric triskelion shape was designed to allow the positioning of building blocks in a precise geometry for closed-capsule structure formation. CPFA consists of even-numbered l-amino acids with alternating hydrophilic and -phobic side chains (Figure 1). In this type of a molecular arrangement, the side chains (R groups at the a-carbon atoms) adopt alternating axial and equatorial positions as a low-energy conformation. In contrast, cyclic peptide structures made up of alternating land d-amino acids, as shown in several synthetic cyclic peptides, can adopt a flat-ring structure as a low-energy conformation in which all of the side chains lie horizontal to the plane of the ring (equatorial). The six-residue CPFA consists of three arginines and three hydrophobic amino acids as hydrophilic and -phobic residues, respectively. The hydrophilic and -phobic residues are placed at alternating positions in order for the adjacent side chains to be located at different faces (axial or equatorial). The guanidinium group in arginine has been found to be a crucial residue for cell-surface binding and penetration of cell-penetrating peptides. 27] The hydrophobic amino acids are tyrosine derivatives modified with long alkyl chains. In addition to CPFA with the perhydrogenated alkyl chain (hCPFA), CPFA with the perfluorinated alkyl chain (fCPFA) was synthesized to take advantage of the “fluorophobic effect”. The fluorophobic effect refers to the super[a] E. K. Chung, Dr. E. Lee, Prof. Dr. M. Lee Center for Supramolecular Nano-Assembly and Department of Chemistry, Seoul National University Seoul 151-747 (Korea) Fax: (+82)2-393-6096 E-mail : [email protected] [b] Prof. Dr. Y.-b. Lim Department of Materials Science and Engineering Yonsei University, Seoul 120-749 (Korea) Fax: (+82)2-365-5882 E-mail : [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200903145.