Phosphorylation dynamics are delicately balanced by kinases and phosphatases, and abnormal protein phosphorylation events may disrupt normal cellular physiology and thus lead to diseases. Recent developments in phosphorylation targeting tools-mostly the small-molecule kinase inhibitors-have changed the treatments for cancers and other diseases. Alternatively, the use of bifunctional modalities offers another approach through an event-driven model with distinct advantages. Here, we highlight advances in bifunctional modalities that modulate protein phosphorylation, including PhosTACs, DEPTACs, PhoRCs, PHICS, and related approaches. Starting with an overview of both kinases and phosphates, we describe recent applications of phosphorylation-targeting therapeutics, with a discussion about the advantages and limitations of current tools, and alternative solutions using bifunctional systems. In addition, the modes of action of various bifunctional modalities and the interplay among protein substrates, kinases, and phosphatases are also discussed, offering an insight into the advancements of phosphorylation targeting strategies against human diseases.

The supramolecular architecture of light-harvesting complex 2 (LH2) and light-harvesting complex 1-reaction center (LH1-RC) complexes underpins the near-unity quantum efficiency of photosynthesis in purple bacteria. Constructing artificial photosynthetic systems that structurally and functionally mimic these natural assemblies remains a critical challenge. Here, we report a spherical chromatophore nanomicelle system that mimics both LH2 and LH1-RC in water. This system is constructed through hierarchical coassembly of an amphiphilic porphyrin-based bacteriochlorophyll analogue and a cationic molecular nickel catalyst. Cryogenic electron microscopy directly resolves high-resolution ring-like structures on the nanomicelle surface, providing the first visual confirmation of the biomimetic architecture. The system achieves photocatalytic hydrogen evolution with a turnover number exceeding 667,000 over 72 h and a turnover frequency of above 9000 h(-1) with an absolute hydrogen yield of 1.34 mu mol- 40 times greater than the nonassembled free molecular system- along with an initial external quantum efficiency of 6.8% at 435 nm. This outstanding performance originates from the well-defined spatial organization of the photosensitizers and catalysts, which facilitates efficient light harvesting and directional energy/electron transfer. Our work establishes a promising strategy for constructing high-performance artificial photosynthetic systems through rational biomimetic design.

Modifications to cyclodipeptides endow this class of natural products with structural diversity and bioactive significance. Herein, we identified a group of natural products, named ditrypzocin A-G, featuring a cyclo-di-l-tryptophan scaffold and N-nitroso modification on the indole moiety through intensive spectroscopic analysis and isotope labeling. In vivo and in vitro investigations revealed that these compounds are biosynthesized by a three-gene cluster, encoding a tRNA-dependent cyclodipeptide synthase, a SAM-dependent methyltransferase, and an acyl-CoA-synthetase-like N-nitrosylase. The N-nitrosation of indole side chain is catalyzed by the N-nitrosylase Mr3558 in an ATP and nitrite-dependent manner, which is a prerequisite to the methylation of the diketopiperazine ring but was neglected in previous study. Molecular docking and site-directed mutagenesis evidenced that a noncanonical substrate binding mode probably accounts for the dedicated catalysis of Mr3558. These findings enlarge the structural diversity of cyclodipeptides and supply a beneficial tool for the discovery and engineering of N-nitroso-containing compounds.

A highly regioselective, one-step lipase-catalyzed method enabled the diversification of rapamycin at its C42 position, producing 10 derivatives (4 novel). Biological screening identified derivative 9 as a potent lead compound with superior antiproliferative activity (IC50 = 6.5 mu M in ACHN cells), outperforming both rapamycin and temsirolimus. This work offers a practical enzymatic route for rapamycin remodeling and highlights a promising mTOR-targeted anticancer candidate.

Inspired by the binary necklace problem in combinatorial mathematics, we designed and constructed a series of metallo-supramolecular polygons via coordination-driven self-assembly (CDSA) of an anisotropic tetratopic terpyridine ligand with Zn(II) ions. Such anisotropic units with two different orientations serve as two types of beads in the assembly process, resulting in supramolecular necklaces that, in theory, exhibit numerous isomers. Through combinatorial analysis, molecular modelling, and experimental validation, we identified three predominant hexameric isomers with distinct symmetrical characteristics. The experimental distribution of these isomers agreed well with their formation probabilities resolved from the binary necklace problem. Notably, detailed structural analysis by scanning tunneling microscopy imaging confirmed the pivotal role of entropy in determining the isomeric distribution. Upon heating under diluted conditions, such three hexameric isomers were transformed into a single pentameric structure as the dominant species, which aligns with the theoretical predictions of binary necklace problem and minimized strain energy. This transformation was corroborated with theoretical modelling and experimental study, highlighting the critical influence of symmetry and entropy in directing the thermodynamic pathway of CDSA. This work provides a notable example of mathematically rationalized supramolecular chemistry, offering profound insights into the thermodynamic aspects of CDSA.

Chiral-at-cage o-carboranes represent a class of three-dimensional boron-cluster-based chiral molecules. Herein, we report a Pd-catalyzed regio- and enantioselective B(4)-H arylation of o-carboranyl benzaldehydes enabled by a chiral transient directing group (cTDG) strategy using l-threonine. The reaction proceeds via reversible imine formation and enantioselective B-H arylation, affording chiral-at-cage products in up to 87% yield and 98% ee. Chiroptical characterizations confirm the potential of the products in optoelectronic materials. This work provides a practical approach to asymmetric B-H functionalization using in-situ-formed cTDGs.