Peptides have gained increasing attention in drug discovery in the past decades due to their moderate molecular weight, inherent biocompatibility, and relatively simple synthetic access. Small molecules have successfully been employed to target well-defined binding pockets of enzymes and other so-called "druggable" targets. However, extended areas on the surface of proteins, postulated to be "undruggable targets" with small molecule modulates. These targets can be addressed with modalities with large surface area like peptides, proteins and antibodies. Unlike biological drugs, which cannot traverse the cell membrane efficiently, peptides can be optimized to be passively permeable, and cyclization is at the core of all designs for increased cell permeability and oral availability. Cyclization of peptides also can minimize proteolytic liability, and decrease conformational flexibility leading to stronger association with cognate targets. Genetically-encoded (GE) libraries displayed on phage , mRNA , bacteria and yeast as well as DNA-encoded libraries (DEL) of macrocyclic topology offer uniquely advantages in discovery of macrocyclic peptides because they associate the unique DNA message with structure of each individual macrocycle. The genotype-phenotype connection allows amplification from a single copy number, repetitive rounds of selection or maturation, and makes it possible to start discovery campaigns from libraries of 10 6 -10 12 scale. Ligands emanating from these campaigns often serve as a starting point for drug discovery. Macrocyclic libraries with unnatural amino acids (UAA) and chemically post-translational modified (cPTM) libraries offer numerous advantage over traditional GEL made from 20 natural amino acids (AA). All de novo UAA/cPTM discoveries today start from completely random naïve UAA/cPTM libraries of >10 9 compounds and they do not use any knowledge from 20 AA libraries. An open question remains: is it advantageous to always start from naïve cPTM/UAA libraries without prior knowledge, or is there a benefit in starting the discovery from libraries with built-in knowledge? Thus, our manuscript explored the potential of discovering chemically modified macrocycles and bicycles by modifying upon existing natural 20AA selection campaigns late stage in discovery.