Genetically Encoding a Lipidated Amino Acid for Extension of Protein Half‐Life in vivo

Protein therapeutics are increasingly used to treat various diseases, yet they often suffer from short serum half‐lives. An emerging strategy to extend lifetime in vivo is to attach fatty acids onto proteins to increase their binding to human serum albumin (HSA). Herein, the genetic encoding of ?‐N‐heptanoyl‐l ‐lysine (HepoK) is reported, which introduces a fatty‐acid‐containing amino acid into proteins with exquisite site‐specificity and homogeneity, overcoming issues associated with existing chemical conjugation methods. The expression in E .coli and purification of HepoK‐incorporated glucagon‐like peptide‐1 (GLP1) is demonstrated. GLP1(HepoK) showed stronger binding to HSA than GLP1(WT), without impairing the stimulation of the GLP1 receptor in cells. Moreover, GLP1(HepoK) decreased blood glucose level to the same level as GLP1(WT) in mice, showing longer‐lasting effects than GLP1(WT). HepoK incorporation will also be useful for investigating the function of protein lipidation.     

An in situ Dynamic Continuum of Supramolecular Phosphoglycopeptides Enables Formation of 3D Cell Spheroids

Higher‐order assemblies of proteins, with a structural and dynamic continuum, is an important concept in biology, but these insights have yet to be applied in designing biomaterials. Dynamic assemblies of supramolecular phosphoglycopeptides (sPGPs) transform a 2D cell sheet into 3D cell spheroids. A ligand–receptor interaction between a glycopeptide and a phosphopeptide produces sPGPs that form nanoparticles, which transform into nanofibrils upon partial enzymatic dephosphorylation. The assemblies form dynamically and hierarchically in situ on the cell surface, and interact with the extracellular matrix molecules and effectively abolish contact inhibition of locomotion (CIL) of the cells. Integrating molecular recognition, catalysis, and assembly, these active assemblies act as a dynamic continuum to disrupt CIL, thus illustrating a new kind of biomaterial for regulating cell behavior.     

Peristome‐Mimetic Curved Surface for Spontaneous and Directional Separation of Micro Water‐in‐Oil Drops

Separation of micro‐scaled water‐in‐oil droplets is important in environmental protection, bioassays, and saving functional inks. So far, bulk oil–water separation has been achieved by membrane separation and sponge absorption, but micro‐drop separation still remains a challenge. Herein we report that instead of the “plug‐and‐go” separation model, tiny water‐in‐oil droplets can be separated into pure water and oil droplets through “go‐in‐opposite ways” on curved peristome‐mimetic surfaces, in milliseconds, without energy input. More importantly, this overflow controlled method can be applied to handle oil‐in‐oil droplets with surface tension differences as low as 14.7 mN m⁻¹ and viscous liquids with viscosities as high as hundreds centipoises, which markedly increases the range of applicable liquids for micro‐scaled separation. Furthermore, the curved peristome‐mimetic surface guides the separated drops in different directions with high efficiency.     

Design of the First‐in‐Class,Highly Potent Irreversible Inhibitor Targeting the Menin‐MLL Protein–Protein Interaction

The structure‐based design of M‐525 as the first‐in‐class, highly potent, irreversible small‐molecule inhibitor of the menin‐MLL interaction is presented. M‐525 targets cellular menin protein at sub‐nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLL‐regulated gene expression in MLL leukemia cells. M‐525 demonstrates high cellular specificity over non‐MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and co‐crystal structure of M‐525 in complex with menin firmly establish its mode of action. A single administration of M‐525 effectively suppresses MLL‐regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize M‐525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.     

Convergent Total Syntheses of (−)‐Rubriflordilactone B and (−)‐pseudo‐Rubriflordilactone B

A highly convergent strategy for the synthesis of the natural product (?)‐rubriflordilactone B, and the proposed structure of (?)‐pseudo‐rubriflordilactone B, is described. Late stage coupling of diynes containing the respective natural product FG rings with a common AB ring aldehyde precedes rhodium‐catalyzed [2+2+2] alkyne cyclotrimerization to form the natural product skeleton, with the syntheses completed in just one further operation. This work resolves the uncertainty surrounding the identity of pseudo‐rubriflordilactone B and provides a robust platform for further synthetic and biological investigations.