Structural diversity in de novo cyclic peptide ligands from genetically encoded library technologies

Tom E. McAllister, Oliver D. Coleman, Grace Roper, Akane Kawamura
2020 Peptide Science  
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
more » ... 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. K E Y W O R D S chemical biology, crystal structures, cyclic peptides, display technologies, drug discovery | INTRODUCTION Cyclic peptides (CPs) are an emerging class of molecules that occupy the 'Goldilocks space between small molecules and large biologics', [1] with the potential to combine the best attributes of antibodies (high specificity and affinity) and small molecules (bioavailability and pharmacokinetics). Thus CPs have recently been attracting significant attention for use in a therapeutic setting [2, 3] and as tools for chemical biology owing to the high specificity and high affinities that they can achieve against a wide range of targets. One of the particularly intriguing properties of CPs is the diversity of the chemical space they can cover and three-dimensional structures they are able to adopt in order to achieve binding to their target protein. Unlike linear peptides, which are conformationally flexible and highly dynamic, the constraint of cyclisation in CPs restricts the number of conformations the peptide chain can adopt, thus reducing the entropic penalty for binding to its target. Small molecules, on the other hand, are typically very conformationally constrained, making them ideal for targeting pockets and presenting binding groups in a defined arrangement, but are limited when targeting large, shallow protein surfaces often considered to be 'undruggable' biological interaction space, such as protein-protein interactions (PPIs).
doi:10.1002/pep2.24204 fatcat:cyi3thj5vveptdigpxhxa3ubzq