Abstract
AbstractCyclic 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.
Highlights
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 and small molecules
Since the first CP phage display was described over 25 years ago,[13] the CP genetically encoded library technologies have transformed the way ligands are generated for protein targets of interest
CPs have successfully been used to target a wide range of different classes of proteins, including ‘difficult’ protein-protein interactions (PPIs)
Summary
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). There are many examples of bioactive CPs found in nature; the fungal natural product cyclosporine is used as an immunosuppressant while phalloidin and α-amanitin are highly toxic to humans.[4] Defined biological activities for these peptides have been elucidated, but rational de novo design of such molecules with desirable properties against targets of interest is highly challenging It is not surprising, that the richest source of CPs (aside from those found naturally occurring) is through genetically encoded library technologies, where diverse starting pools of combinatorial peptides that cover vast chemical space can rapidly be generated and screened to identify CPs that efficiently bind to a target of interest. We will not cover peptides that are designed to be α-helical, such as stapled peptides, since, by definition, these will form an α-helix and have minimal variation in their structures
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