Construction of Phospholipid-Like Vesicles by Aqueous Aminolysis of Acyl Thioesters With Diamino Acids

Abstract

[Abstract] Membrane-forming phospholipids are produced in cells by enzymatic diacylation of polar head groups. However, analogousnonenzymatic processes remain both challenging and limited in scope. Moreover, the restricted variety of canonical lipidhead groups constrains the properties and functions of phospholipid membranes. Therefore, the development of chemicalmethodologies for the straightforward preparation of versatile membrane-forming building blocks is highly valuable. Here, wedescribe a simple strategy for the aqueous synthesis of phospholipid-like molecules via direct aminolysis between diaminoacids and water-soluble acyl thioesters. In the presence of imidazole, diamino acids (i.e., diaminopropionic acid, ornithine,lysine) undergo rapid N-diacylation to yield amphiphilic diacylated amino acids (DAAAs). These amino acid-lipid conjugatesspontaneously self-assemble into robust micron-sized vesicular structures capable of encapsulating hydrophilic cargos across awide pH and temperature range. Our findings highlight the potential of amino acid-based lipids as modular, functional buildingblocks for generating tunable membranous systems in aqueous environments.