Design and Synthesis of Boron-Containing Noncanonical Amino Acids With Enhanced Stability and Solubility

Abstract

The development of noncanonical amino acids (ncAAs) provides a powerful strategy to expand the chemical space of proteins beyond the natural repertoire, thereby overcoming intrinsic pharmacodynamic limitations of peptides and proteins. Among these, boron-containing ncAAs are of particular interest due to the versatile reactivity of boron and its proven therapeutic relevance in clinically approved drugs. However, poor aqueous solubility, instability under physiological conditions, and oxidative degradation have hindered their broader biological application. Here, we report the design and synthesis of a new class of boron-containing ncAAs with enhanced solubility and stability. Structural modifications around the boron center and optimized substituents were employed to improve compatibility with biological systems while retaining functional reactivity. Moreover, fluorescence analysis revealed distinct photophysical properties, indicating potential applications in protein engineering and biosensing. These results highlight the utility of cyclic boron architectures as a versatile platform for the development of boron-based amino acid analogs with broad implications in chemical biology, drug discovery, and biomolecular design.