Fluorous Phase‐Directed Peptide Assembly Affords Nano‐Peptisomes Capable of Ultrasound‐Triggered Cellular Delivery

Here, we report the design, synthesis and efficacy of a new class of ultrasound (US)‐sensitive self‐assembled peptide‐based nanoparticle. Peptisomes are prepared via templated assembly of a de novo designed peptide at the interface of fluorinated nanodroplets. Utilizing peptide assembly allows for facile particle synthesis, direct incorporation of bioactive sequences displayed from the particle corona, and the ability to easily encapsulate biologics during particle preparation using a mild solvent exchange procedure. Further, nano‐peptisome size can be precisely controlled by simply modulating the starting peptide and fluorinated solvent concentrations during synthesis. Biomolecular cargo encapsulated within the particle core can be directly delivered to the cytoplasm of cells upon US‐mediated rupture of the carrier. Thus, nano‐peptisomes represent a novel class of US‐activated carriers that can shuttle cell‐impermeable biomacromolecules into cells with spatial and temporal precision.     

On the Role of Chirality in Guiding the Self‐Assembly of Peptides

Homochirality in peptides is crucial in sustaining “like–like” intermolecular interactions that allow the formation of assemblies and aggregates and is ultimately responsible for the resulting material properties. With the help of a series of stereoisomers of the tripeptide F–F–L, we demonstrate the critical role that peptide stereochemistry plays in the self‐assembly of peptides, guided by molecular recognition, and for self‐sorting. Homochiral self‐assemblies are thermally and mechanically more robust compared to heterochiral self‐assemblies. Morphological studies of the multicomponent peptide systems showed that aggregates formed from homochiral peptides possessed a uniform nano‐fibrous structure, whereas heterochiral systems resulted in self‐sorted systems with a heterogeneous morphology. In essence, homochiral peptides form the stronger aggregates, which may be one of reasons why homochirality is preferred in living systems.     

Real‐Time In‐Situ Monitoring of a Tunable Pentapeptide Gel–Crystal Transition

Supramolecular gels often become destabilized by the transition of the gelator into a more stable crystalline phase, but often the long timescale and sporadic localization of the crystalline phase preclude a persistent observation of this process. We present a pentapeptide gel–crystal phase transition amenable for continuous visualization and quantification by common microscopic methods, allowing the extraction of kinetics and visualization of the dynamics of the transition. Using optical microscopy and microrheology, we show that the transition is a sporadic event in which gel dissolution is associated with microcrystalline growth that follows a sigmoidal rate profile. The two phases are based on β‐sheets of similar yet distinct configuration. We also demonstrate that the transition kinetics and crystal morphology can be modulated by extrinsic factors, including temperature, solvent composition, and mechanical perturbation. This work introduces an accessible model system and methodology for studying phase transitions in supramolecular gels.     

Application of Methyl Bisphosphine‐Ligated Palladium Complexes for Low Pressure N‐11C‐Acetylation of Peptides

A mild and effective method is described for ¹¹C‐labeling of peptides selectively at the N‐terminal nitrogen or at internal lysine positions. The presented method relies on the use of specific biphosphine palladium–methyl complexes and their high reactivity towards amino‐carbonylation of amine groups in the presence [¹¹C]carbon monoxide. The protocol facilitates the production of native N‐¹¹C‐acetylated peptides, without any structural modifications and has been applied to a selection of bioactive peptides.     

Stapled Peptides by Late‐Stage C(sp3)−H Activation

Despite the importance of stapled peptides for drug discovery, only few practical processes to prepare cross‐linked peptides have been described; thus the structural diversity of available staple motifs is currently limited. At the same time, C−H activation has emerged as an efficient approach to functionalize complex molecules. Although there are many reports on the C−H functionalization of amino acids, examples of post‐synthetic peptide C−H modification are rare and comprise almost only C(sp²)−H activation. Herein, we report the development of a palladium‐catalyzed late‐stage C(sp³)−H activation method for peptide stapling, affording an unprecedented hydrocarbon cross‐link. This method was first employed to prepare a library of stapled peptides in solution. The compatibility with various amino acids as well as the influence of the size (i ,i +3 and i ,i +4) and length of the staple were investigated. Finally, a simple solid‐phase procedure was also established.     

Orthogonal Halogen‐Bonding‐Driven 3D Supramolecular Assembly of Right‐Handed Synthetic Helical Peptides

Peptide‐mediated self‐assembly is a prevalent method for creating highly ordered supramolecular architectures. Herein, we report the first example of orthogonal C?X???X?C/C?X???π halogen bonding and hydrogen bonding driven crystalline architectures based on synthetic helical peptides bearing hybrids of l ‐sulfono‐γ‐AApeptides and natural amino acids. The combination of halogen bonding, intra‐/intermolecular hydrogen bonding, and intermolecular hydrophobic interactions enabled novel 3D supramolecular assembly. The orthogonal halogen bonding in the supramolecular architecture exerts a novel mechanism for the self‐assembly of synthetic peptide foldamers and gives new insights into molecular recognition, supramolecular design, and rational design of biomimetic structures.     

Translating Thermal Response of Triblock Copolymer Assemblies in Dilute Solution to Macroscopic Gelation and Phase Separation

The thermal response of semi‐dilute solutions (5 w/w%) of two amphiphilic thermoresponsive poly(ethylene oxide)‐b ‐poly(N ,N ‐diethylacrylamide)‐b ‐poly(N ,N ‐dibutylacrylamide) (PEO₄₅‐PDEAm_x‐PDBAm₁₂) triblock copolymers, which differ only in the size of the central responsive block, in water was examined. Aqueous PEO₄₅‐PDEAm₄₁‐PDBAm₁₂ solutions, which undergo a thermally induced sphere‐to‐worm transition in dilute solution, were found to reversibly form soft (G ′≈10 Pa) free‐standing physical gels after 10 min at 55 °C. PEO₄₅‐PDEAm₈₉‐PDBAm₁₂ copolymer solutions, which undergo a thermally induced transition from spheres to large compound micelles (LCM) in dilute solution, underwent phase separation after heating at 55 °C for 10 min owing to sedimentation of LCMs. The reversibility of LCM formation was investigated as a non‐specific method for removal of a water‐soluble dye from aqueous solution. The composition and size of the central responsive block in these polymers dictate the microscopic and macroscopic response of the polymer solutions as well as the rates of transition between assemblies.