Posttranslational modification of proteins expands their structural and functional capabilities beyond those directly specified by the genetic code. However, the vast diversity of chemically plausible (including unnatural but functionally relevant) side chains is not readily accessible. We describe C (sp)-C (sp) bond-forming reactions on proteins under biocompatible conditions, which exploit unusual carbon free-radical chemistry, and use them to form Cβ-Cγ bonds with altered side chains. We demonstrate how these transformations enable a wide diversity of natural, unnatural, posttranslationally modified (methylated, glycosylated, phosphorylated, hydroxylated), and labeled (fluorinated, isotopically labeled) side chains to be added to a common, readily accessible dehydroalanine precursor in a range of representative protein types and scaffolds. This approach, outside of the rigid constraints of the ribosome and enzymatic processing, may be modified more generally for access to diverse proteins.

In any drug discovery effort, the identification of hits for further optimisation is of crucial importance. For peptide therapeutics, display technologies such as mRNA display have emerged as powerful methodologies...

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.

We demonstrate that the volume phase transition temperature (VPTT) of copolymer microgel particles made from N‐isopropylacrylamide (NIPAm) and methacryloyl hydrazide (MH) can be tailored in a reversible manner upon the reaction of the hydrazide functional groups with aldehydes. The microgels were synthesized by precipitation polymerization in water. Due to the water‐soluble nature of the MH monomer, the VPTT at which the microgel particles contract shifts to higher values by increasing the incorporated amounts of methacryloyl hydrazide from 0 to 5.0 mol %. The VPTT of the copolymer microgel dispersions in water can be fine‐tuned upon addition of hydrophobic/hydrophilic aldehydes, which react with the hydrazide moiety to produce the hydrazone analogue. This hydrazone formation is reversible, which allows for flexible, dynamic control of the thermo‐responsive behavior of the microgels. The ability to “switch” the VPTT was demonstrated by exposing hydrophilic streptomycin sulfate salt incubated microgel particles to an excess of a hydrophobic aldehyde, that is benzaldehyde. The temperature at which these microgels contracted in size upon heating was markedly lowered in these aldehyde exchange experiments. Transformation into benzaldehyde hydrazone derivatives led to assembly of the microgel particles into small colloidal clusters at elevated temperatures. This control of supracolloidal cluster formation was also demonstrated with polystyrene particles which had a hydrazide functionalised microgel shell. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 1745–1754