Post-translational modifications (PTMs) greatly expand the structures and functions of proteins in nature 1,2 . Although synthetic protein functionalization strategies allow mimicry of PTMs 3,4 , as well as formation of unnatural protein variants with diverse potential functions, including drug carrying 5 , tracking, imaging 6 and partner crosslinking 7 , the range of functional groups that can be introduced remains limited. Here we describe the visible-light-driven installation of side chains at dehydroalanine residues in proteins through the formation of carbon radicals that allow C-C bond formation in water. Control of the reaction redox allows site-selective modification with good conversion efficiencies and reduced protein damage. In situ generation of boronic acid catechol ester derivatives generates RH2C • radicals that form the native (β-CH2-γ-CH2) linkage of natural residues and PTMs, whereas in situ potentiation of pyridylsulfonyl derivatives by Fe(II) generates RF2C • radicals that form equivalent β-CH2-γ-CF2 linkages bearing difluoromethylene labels. These reactions are chemically tolerant and incorporate a wide range of functionalities (more than 50 unique residues/side chains) into diverse protein scaffolds and sites. Initiation can be applied chemoselectively in the presence of sensitive groups in the radical precursors, enabling installation of previously incompatible side chains. The resulting protein function and reactivity are used to install radical precursors for homolytic on-protein radical
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.
Cyclic peptides are an exciting class of compounds that are currently underexploited as chemical probes. Recent advances in peptide chemistry, screening and sequencing technologies have permitted the efficient generation and screening of natural product-like cyclic peptide libraries to identify high-affinity and -selectivity ligands against targets of interest, providing new opportunities for the development of chemical probes, including for challenging targets. This chapter reviews recent advances in cyclic peptide technologies and provides examples where cyclic peptides have been used to study the biology of their targets.
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