From the first clinical application of insulin in 1921 to the recent triumph of GLP-1 agonists , peptides have proven a valuable therapeutic modality. Advances in genetic code reprogramming, biological display, and computational design have set the stage for the next generation of peptide-derived therapeutics . The first wave of these compounds represent some of the most exciting therapeutic candidates of the past decade because of their antibody-like affinity for traditionally "undruggable" targets such as protein-protein interfaces, while also showing promise for oral or intracellular delivery. Several therapeutic candidates derived from de novo peptide leads have progressed into clinical trials or onto the market . In each of these cases, the initial lead identified by mRNA or phage display required extensive modification to improve its physicochemical properties . Modifications introduced during lead optimization often include the installation of one or more macrocyclic rings and other backbone alterations that enhance protease resistance, target affinity, bioavailability, and/or cell permeability . Chemical strategies to install these modifications earlier in the drug discovery process-ideally, prior to biological display-would offer distinct advantages.