Tailoring of Peptide Vesicles: A Bottom-Up Chemical Approach

CONSPECTUS: Spherical ordering from small molecules is a subject of intense interest to chemists. The inherent capability of amphiphiles to assemble spontaneously is the unique feature of the evolutionary process of life. Self-assembly is prevalent in biology and has attracted the interest of scientists across several disciplines. This is because scientists have realized that nature has extensively used this inherent organizational power contained in the molecules. Judicious use of the self-assembly principle is the cornerstone of nature's exotic assemblies. These exotic assemblies lead to unimaginable functions in biology that might not have been predicted from the monomer building blocks alone. Recently, a number of chemical systems that self-assemble in aqueous or organic solvents to form vesicles were reported. This account provides advances made from our laboratory toward designing and understanding the mechanism of formation of spherical vesicular assembly. A bottom-up approach for the de novo design of vesicles using nonlipidated molecular architecture will be a paradigm shift in vesicular research. Vesicles act as a protocell model for studying the origin and evolution of cellular life. They could also act as excellent model systems for studying the fusion of cells and membrane transport. Self-assembled vesicles have enormous potential for several applications such as drug and biomolecule delivery to cells and in materials science. These aspects along with the dynamic nature of vesicular assembly have attracted researchers to the study of spherical assemblies. The common belief was that the molecules that form vesicles must have one polar head and two hydrophobic tails. All attempts to synthesize vesicles are by mimicking nature's strategy, which mainly involves the self-assembly of lipid amphiphiles through a bilayer-like arrangement. Pseudopeptide-based molecules with the ability to form vesicles have changed this long-standing notion. In addition to chemical and medical applications, these peptide vesicles could act as models for protocells, membrane fusion, and the study of the vesiculation mechanism. This Account highlights the progress made toward a heuristic approach to the de novo design of vesicles using pseudopeptides as building blocks. A large number of diverse classes of pseudopeptides showed vesicular assembly. Various acyclic and cyclic molecules were designed and synthesized that showed spherical vesicular assembly. Cystine-based macrocyclic peptides showed drug encapsulation and release. Polymersomes with unusual topology, self-assembling tripodal ligands, and molecules containing amino acids such as lysine, leucine, cystine, and serine were synthesized. The incorporation of a wide variety of amino acids in the vesicle-forming peptides could enhance their scope and applications. The mechanism of vesiculation was also investigated using these designer molecules.

Automated summary

The spontaneous self-assembly of amphiphiles is a unique feature in biological evolution, attracting scientists from various disciplines to study nature's organizational power. Recent advances have been made in designing and understanding the mechanism of spherical vesicular assembly. Nonlipidated molecular architecture for vesicle design represents a paradigm shift in vesicular research, with potential applications in drug delivery, biomolecule transport, and materials science. Pseudopeptide-based molecules have challenged traditional notions of vesicle formation, offering new insights into protocell models, membrane fusion, and vesiculation mechanisms.