The application of fluorinated α-amino acids to drug discovery techniques

While fluorinated amino acids (FAAs) have been utilized for the discovery and development of both small molecules and therapeutic peptides, it is important to also recognize the stand-alone value of these entities. The ability of fluorine to replace hydrogen in naturally occurring amino acids (or indeed be incorporated in unnatural/novel amino acids) without a significant perturbation in the steric properties of the molecule allows direct substitutions to seamlessly occur, while the 'unique' nature of the fluorine atom itself allows these 'analogues' to be utilized in biological systems.

This review discusses several areas where fluorinated amino acids (FAAs) have been directly employed within drug discovery. While by no means comprehensive, the examples and case studies described are intended not only to demonstrate current applications but also to illustrate both the vast potential and the array of challenges that still arise in these areas.

While progress has been made, there is substantial room for growth and innovation in each field. For example, a better understanding of the factors critical in defining the selectivity and kinetics of irreversible enzyme inhibition should enable better FAA-based derivatives to be designed to further probe these entities as therapeutics. While the examples presented here utilize the fluorine in both the design and imaging element of a single theranostic agent, complementing techniques, such as ¹⁹F-NMR with cryo-EM for fragment-based drug discovery, provide a compelling path for more efficient drug discovery.