Peptides occupy a privileged space in drug development, often exhibiting higher target specificity, lower toxicity and higher binding affinities than small molecule drugs, leading to far fewer side effects. However, the use of peptides as drugs has been limited by their poor bioavailability, in part due to their susceptibility to proteolytic degradation, which decreases the half-life of peptide therapies. The cyclisation of linear peptides has been shown to enhance stability by increasing resistance to both endo- and exoproteases. Although numerous techniques are available for peptide cyclisation, many methods rely on the incorporation of modified or unnatural amino acids, which can be both expensive or synthetically challenging. Strategies which leverage the inherent reactivity of proteinogenic amino acids for the direct cyclisation of unprotected precursors represent attractive alternatives. This presentation will detail our efforts toward the development of a linker-based reductive amination approach to the cyclisation of unprotected peptides bearing amine functionalities at the side-chain and/or N-terminal positions. Building off prior work on the head-to-tail macrocyclisation of peptide aldehydes, we disclose the synthesis of a library of cyclic peptides via reaction of various 4-substituted-2,6-pyridinedialdehyde linkers with peptide diamines. Screening of solvent systems, reductants, and reactant stoichiometries enabled optimisation of the cyclisation reaction. The imine intermediate forms rapidly under mild conditions and the subsequent reduction proceeds to afford stable, 2,6-pyridinediamine cyclised peptides. The 4-substituted-pyridine macrocycles are amenable to conjugation using CuAAC chemistry, thus enabling further modification through bioconjugation, glycosylation and fluorescent labelling. This cyclisation method therefore provides a mild and selective approach to the direct late-stage modification of linear peptides and could provide a promising pathway to cyclic peptide-based therapeutics.