Orally bioavailable macrocyclic peptides have the potential to unlock a new paradigm in drug discovery, enabling monoclonal antibody-like potency and selectivity despite 100X smaller molecular weight. mRNA display screening technology has enabled identification of lead chemical matter that can inhibit binding of PCSK9 to the LDL receptor. This lead needed to be optimized via extensive structure-activity relationship studies to deliver exquisite potency and selectivity for PCSK9. To achieve this, extensive advances in synthetic methods and strategy were developed in order to enable discovery of a clinical candidate. Further process chemistry optimization was used to scale-up this lead-molecule, including novel biocatalytic methods to access key non-canonical amino acids. This presentation will cover the extensive synthetic work to achieve the synthesis and large scale manufacture of MK-0616. The successful application of these synthetic chemistry advances pave the way for application to other important protein-protein interaction targets.