Chemoenzymatic Approaches for the Late-Stage Functionalisation of Therapeutic Peptides

The use of peptides as effective therapeutics is a rapidly growing area, with over 30 candidates approved for clinical use since 2000. Peptides have been shown to be highly efficacious, selective and potent therapeutics for a wide range of diseases including type 2 diabetes and the inhibition of protein-protein interactions that were previously undruggable with traditional small molecule drug candidates.

Despite providing promising avenues for new therapeutic and diagnostic agents, peptides suffer from a range of drawbacks that limit their application including enzymatic degradation, rapid clearance by the renal system, poor membrane permeability and poor oral availability. Therefore, effective methods for the modification of peptide scaffolds are needed to improve their pharmacological properties before they can be applied in the clinic.

Currently, methods for modulating the pharmacological properties of peptide drug leads rely on utilising nucleophilic sites within the proteome such as cysteine, lysine or the free amine at the N-terminus of the peptide. Through these sites, a wide range of features can be installed including new groups that can improve lipophilicity and membrane permeability, non-proteinogenic chemical handles for further downstream functionalisation and structural features such as macrocyclisation that can limit enzymatic degradation. Transition metal-mediated C-H functionalisation methods are also routinely applied across the literature to target typically unreactive aliphatic and aromatic residues.

Despite the widespread application of these approaches, limitations exist relating to green and sustainable chemical practices. These methods are also generally poor from a regio or chemoselective viewpoint if multiple reactive sites are present, with reduced yields of the desired product and the creation of waste byproducts. Additionally, many of these also rely on environmentally damaging solvents or increasingly scarce catalytic materials. Therefore, new, sustainable, site-selective modification strategies are highly desirable.