Utility of fluorinated α-amino acids in development of therapeutic peptides

Fluorinated amino acids are at the focal point of two key current strategic areas within drug discovery being both important for the design/development of new small molecule drugs as well as having the potential to be exploited in the rapidly expanding area of peptide-based therapeutics. While the challenges of developing therapeutic peptides are relatively well understood and strategies have been developed to overcome these, the utilization of fluorinated amino acids for this purpose appears to be relatively sparse, particularly in progressing peptide derivatives into clinical development.

This review discusses the applications of fluorinated amino acid (FAA) derivatives in modern drug discovery with a specific focus on their incorporation into therapeutic peptide derivatives, based on the currently available literature.

While only one naturally occurring and fluorinated amino acid (FAA) is known, the use of this class of compounds is prevalent in drug discovery campaigns. Synthetic advances have allowed ready access to a diverse range of compounds featuring this structural motif, and the bifunctional modularity of the amino and carboxylic acid moiety typically allows their ready incorporation into novel molecular entities through well-precedented chemistries. However, caution should be exercised when FAAs are utilized in solid-phase peptide synthesis (SPPS) as the electronegativity of the fluorine substation often mitigates the reactivity of the system leading to poor yields. Future efforts should look toward developing a more reliable understanding of the impact of these changes to enable a robust platform for therapeutic peptides to be designed based on the incorporation of fluorinated amino acids.