Chapter 9: Genetically Encoded Cyclic Peptide Libraries

Inhibitor discovery has traditionally been conducted with small-molecule libraries, but the recent development of several technologies has enabled the use of macrocyclic peptide libraries for this purpose. Although these compounds are thought to have the potential for highly specific target engagement and low toxicity, they suffer from the same criticisms directed at linear peptides in drug discovery: they are not drug-like, cannot be readily translated into small molecules, and are neither cell-permeable nor orally bioavailable. However, counterarguments for cyclic peptides point to their limited conformational freedom as being of significant benefit when compared against their linear counterparts, in terms of improved affinity, metabolic stability and proposed improvements in cell permeability. As a result, a competing school of thought has emerged, promoting cyclic peptides as being privileged scaffolds for drug discovery, particularly against “undruggable” targets such as protein–protein interactions (PPIs). Here, we will discuss the several platforms that use genetic encoding for the production of cyclic peptide libraries, whilst providing a detailed evaluation of the advantages and disadvantages of their implementation.