Structural diversity inde novocyclic peptide ligands from genetically encoded library technologies

Abstract

Cyclic peptides discovered by genetically encoded library technologies have emerged as a class of promising molecules in chemical biology and drug discovery. Here we review the cyclic peptides identified through these techniques reported in the period 2015 to 2019, with a particular focus on the three‐dimensional structures that peptides adopt when binding to their targets. A range of different structures have been revealed through co‐crystal structures, highlighting how versatile and adaptable these molecules are in binding to diverse protein targets, such as enzymes and receptors, or challenging shallow surfaces involved in protein‐protein interfaces. Analysis of the properties of the peptides reported shows some interesting trends, with further insight for those with structural information suggestive that larger peptides are more likely to adopt secondary structure. We highlight examples where co‐crystal structures have informed the key interactions that promote high affinity and selectivity of cyclic peptides against their targets, identified novel inhibitor binding sites, and provided new insights into the biology of their targets. The structure‐guided modifications have also aided the design of cyclic peptides with improved activity and physicochemical properties. These examples highlight the importance of crystallography in future cyclic peptide drug discovery initiatives.

Property‐Driven Development of Passively Permeable Macrocyclic Scaffolds Using Heterocycles**

“…[35][36][37] However, the physicochemical properties of the leads generated by library methods can be highly variable, especially if they contain all-L amino acids or polar side chains. [38,39] In the present paper we demonstrate the application of this strategy to 18-membered rings, an important and diverse class of peptide macrocycles. [40]…”

Gold(I)-Mediated Rapid Cyclization of Propargylated Peptides via Imine Formation

“…While biological approaches allow for the rapid discovery of cyclic peptides from large libraries, 4 − 8 their laboratory synthesis can be challenging. The reduced entropy upon cyclization is a major impediment for the synthesis of cyclic peptides, in addition to other issues such as C-terminal epimerization and oligomerization.…”

“…While biological approaches allow for the rapid discovery of cyclic peptides from large libraries, − their laboratory synthesis can be challenging. The reduced entropy upon cyclization is a major impediment for the synthesis of cyclic peptides, in addition to other issues such as C-terminal epimerization and oligomerization. , Moreover, the incorporation of nonpeptidic scaffolds into macrocycles is highly desirable for tuning the cyclic peptide activity and physical properties .…”

Property-driven development of privileged macrocyclic scaffolds using heterocycles

“…[24][25][26] However, the physicochemical properties of the leads generated by library methods can be highly variable, especially if they contain all-L amino acids or polar side chains. 27,28 Given the struggles associated with low cellular permeability of large peptide molecules, a privileged scaffold must engender a reasonably permeable starting point for further structure/activity studies. In the present paper we demonstrate the application of this strategy to 18-membered rings, an important and diverse class of peptide macrocycles.…”