Nearly all cyclic peptides found from ribosomally synthesized library techniques; e.g. phage display and mRNA display, are too large and far too polar for cell permeability. To overcome this, we have utilized a non-traditional medicinal chemistry approach focused on large leaps in scaffold and pharmacophore space. A model medicinal chemistry campaign will be discussed utilizing our chemistry and computational platform. Through the use of iterative focused libraries and direct-to-biology screening we rapidly optimized a series of MDM2 binding cyclic peptides from unobservable intrinsic permeability to small-molecule-like permeability while improving potency 100-fold, yielding compounds with nM cell activity. Efforts to improve the drug-likeness of de novo peptide ligands through macrocycle DNA-encoded libraries, will also be discussed.