Synthesis and characterisation of chemically modified macrocyclic peptide ligands of serum albumin

Bioactive peptides play a crucial role in human health and are involved in diverse biological activities. Peptides offer several advantages over small molecules as therapeutics, such as high selectivity and potency that often result in lower toxicity and fewer side effects. Since the isolation of the peptide hormone insulin in 1921, considerable efforts have been made in the discovery, synthesis, and modification of peptide therapeutic molecules for the treatment of multiple diseases. However, the clinical application of peptide-based drugs is often limited by their rapid elimination from the body. To date, various strategies have been explored to improve the half-life of peptide therapeutics. One of the most promising is the use of the natural plasma protein albumin as a drug delivery protein. Albumin exhibits two key features that make it an ideal drug carrier: i) the ability to bind with good affinity a wide range of endogenous compounds, such as fatty acids, and ii) an intrinsically long half-life of approximately 19 days. The aim of this work is the synthesis, modification and characterisation of several macrocyclic peptide ligands designed to bind albumin with high affinity, which allow the improvement of the pharmacokinetic properties of drug conjugates.