Together forever? Functional selection was applied to finally achieve separation of the analgesic properties of opiods from serious side effects such as potentially lethal respiratory depression. A Gi-biased μ-opioid-receptor agonist (PZM21) was identified that stabilizes previously unexplored receptor conformations. This compound relieves pain in mice without causing hypoventilation or addiction.

First and foremost: Margaret Dayhoff's 1966 hypothesis on the origin of proteins is now an accepted model for the emergence of large, globular, functional proteins from short, simple peptides. However, the fundamental question of how the first protein(s) emerged still stands. The tools and hypotheses pioneered by Dayhoff, and the over 65 million protein sequences and 12 000 structures known today, enable those who follow in her footsteps to address this question.

Transcription unlimited: In the 10 years since the Nobel Prize in Chemistry was awarded to Roger Kornberg for his studies of the molecular basis of transcription, significant advances have been made in our understanding of many aspects of transcription, and progess in cryo-electron microscopy has enabled the study of large molecular assemblies at high resolution. Our current understanding of the structural basis of transcription is discussed in this Minireview.

Persistence pays off: After more than 40 years of effort, promising results are finally being reported the field of Ras inhibition. This Minireview presents the latest advances towards Ras inhibitors, as well as a critical assessment from a medicinal chemistry perspective. The picture shows the covalent inhibitor ARS-853 in complex with K-Ras^G12C.

Making the right choice: Deriving structural information from experimentally measured data is a process beset with theoretical and practical problems. The effects of the various assumptions and approximations involved in the process of biomolecular structure determination are discussed and a list of choices to be avoided is provided.

The sum of its parts: A computational study shows that using mixed linkers within zeolitic imidazolate frameworks provides a route for tuning their electronic gaps and band edge positions. It is theoretically possible in this way to match the electronic structure requirements for photocatalytic reactions including water splitting and CO₂ reduction.

The phytochrome photocycle: The cyanobacterial phytochrome Cph1 regulates cellular processes through light. Dynamic nuclear polarization enhanced solid-state magic-angle spinning NMR spectroscopy was applied to illuminate the mechanism of phytochrome molecular action. The approach enables the assignment of the phycocyanobilin (PCB) chromophore resonances, which allowed localization of the positive charge in PCB.

Beyond mixing: The proper combination of non-isostructural metal–organic frameworks in terms of solid solutions can drastically improve the porosity (150 %) and optical O₂ sensitivity (410 times) compared with the original phases. An oxygen-sensing MOF (MAF-2) can undergo structure changes and property improvements when its molecular building blocks are mixed and solid solutions are formed.

Bioorthogonal probes were developed to study MDM2-p53 inhibitors in an osteosarcoma cell model. Target engagement of the probe, target upregulation upon MDM2-p53 inhibition, and target occupancy of non-tagged MDM2-p53 inhibitors could be monitored by using high-content screening assays and automated single-cell imaging analysis.

Seven new zinc–transition-metal hydrides have been prepared and crystallographically characterized. Through variation of the transition-metal fragment, a series of snapshots of the reaction coordinate of the approach of the Zn−H bond toward the transition-metal is obtained. The reaction trajectory is characterized by the transfer of electron density from the largely ionic Zn−H bond to increasingly covalent TM−H and TM−Zn bonds.

Colloidal self-assembly of atomically precise, monodisperse gold nanoclusters to 2D crystalline nanosheets is reported. The nanosheets bend to closed shells and form spherical capsids.

Density matters: Four different metal nanoparticles with the same size and surface chemistry but different densities were synthesized. It was then shown that the renal clearance of ultrasmall metal nanoparticles decreases exponentially with an increase in particle density while tumor targeting linearly increases.

Insight into host-guest interactions: Using a combination of experimental and computational techniques, template–framework interactions have been probed in a variety of zeolites. The findings demonstrate that the phase that crystallizes is determined by a complex interplay of framework inorganic elements, template conformation, template–heteroatom interactions and framework stabilization by the space-filling template molecules.

Switching surfaces: A metal–organic framework, based on 2D layers of Zn₄(bdc)₂ connected through a pillaring hydrophobic carborane-based linker, switches from hydrophobic to superhydrophilic and vice versa, upon chemical treatment.

Rhodium single-atom catalysts supported on ZnO nanowires display olefin hydroformylation efficiency comparable to that of homogeneous Wilkinson's catalyst.

A synthetic route to a high-performance Li₂GeO₃ anode as a carbon-coating-free electrode for lithium-ion batteries has been developed. The Li₂GeO₃ material consists of micrometer-sized porous clusters, which is beneficial for both faster ion diffusion and electron transfer. The Li₂GeO₃ electrode exhibits long-term cycling stability and high charge capacity.

Shaping proteins: The ferritin cage exhibits high selectivity and has been utilized as a delivery vehicle for anticancer drugs or imaging agents. However, its assembly has been limited to a single size and shape. By tuning the interfacial interaction of recombinant human H-chain ferritin (rHuHF) subunits through amino acid residues insertion, a novel, lower symmetrical ferritin-like nanocage was produced and crystallographically investigated.

Record-breaking: A monometallic dysprosium complex, [Dy(O^tBu)₂(py)₅][BPh₄], displaying near-perfect pentagonal bipyramid geometry defined by two strong axial tert-butoxide ligands and five weak equatorial pyridine donors is reported. This complex displays massive magnetic anisotropy, approaching the limit of a two-coordinate complex, with an energy barrier to magnetic relaxation of U_eff=1815(1) K and a blocking temperature of T_B=14 K.

CO₂ transformation on strategy: Strategic utilization of N-phosphine oxide-substituted imidazolylidenes enabled a direct preparation of a novel carboxylic–phosphinic mixed anhydride from CO₂, which was followed by efficient derivatization into a variety of carbonyl compounds.

Drug delivery: Membrane-impermeable, photoresponsive conjugates have been developed that can be inserted into and retained by membrane-enclosed compartments. Illumination generates a membrane-permeable biologically active agent, which is rapidly secreted. The wavelength of photorelease can be unambiguously pre-assigned, enabling the specific discharge of different bioagents from a common carrier.

Overlaid concentration profiles: The order in any component of a reaction is determined by visual comparison of variably normalized concentration profiles. Variable time normalization analysis (VTNA) is easy and quick to perform, is run under synthetically relevant conditions, and provides information on the entire reaction course.

Crystallization from a multicomponent mixture requires additional steps for product purification. The application of an inhomogeneous electric field on a mixed suspension enables simultaneous particle separation and crystal growth. Crystals of the two solutes (CAF=caffeine, PHE=phenazine) are then separately collected from the two electrodes.

Sponge worthy: The unique combination of crotyl chloride, LiCl, and proton sponge has delivered the first enantio-, diastereo-, and regioselective iridium-catalyzed allylic alkylation reaction to form an all-carbon quaternary stereocenter with an aliphatic-substituted electrophile. The reaction proceeds with good to excellent selectivity for a range of substituted tetralones, providing products bearing a newly formed vicinal tertiary and all-carbon quaternary stereodyad.

One ring to rule them all … and in the darkness bind them: A photoresponsive tetracationic macrocycle features a facile three-step synthesis and makes possible the noncovalent binding of a set of guest molecules, including N-oxide and carboxylate derivatives. The guest molecules can be actively released by UV light irradiation in a remote fashion.

Worth its salt: An efficient regioselective ortho-chlorination of anilines is described. A secondary ammonium chloride salt is employed as the organocatalyst and the reaction can be conducted at room temperature without protection from air and moisture. This catalytic protocol has broad substrate scope, is scalable, and was applied to the efficient synthesis of a potent c-Met kinase inhibitor. DCDMH=1,3-dichloro-5,5-dimethylhydantoin.

Gliding around: A polymer bilayer is able to undergo reversible transitions between flat and tube-like shapes, which allows the externally controlled retention and release of gliding microtubules. These findings open new possibilities to control biomolecular transport using substrates with switchable shapes.

Chiral cyclopropanes à la carte: Myoglobin-based cyclopropanation catalysts featuring complementary stereoselectivity were developed for the synthesis of 1-carboxy-2-aryl-cyclopropanes. The engineered hemoproteins were applied in whole-cell reactions to afford cyclopropane-containing drugs and precursors thereof at the gram scale, in high yield, and with excellent diastereo- and enantioselectivity.

I want a new drug: PCPA-drug conjugates (PDCs) were designed as the basis of a new prodrug strategy. The prototype PCPA-tamoxifen conjugates 1 a and 1 b released 4-hydroxytamoxifen upon inhibition of LSD1. While 1 a and 1 b exhibited antiproliferative activity in breast cancer cells through the simultaneous inhibition of LSD1 and ERα, no cytotoxicity was observed in normal cells.

Feedstocks to building blocks: Transfer hydrogenative coupling of styrene with primary alcohols using the precatalyst HClRu(CO)(PCy₃)₂ modified by AgOTf or HBF₄ delivers branched or linear adducts from benzylic or aliphatic alcohols, respectively. Related 2-propanol mediated reductive couplings also are described.

Save the best for last: The postsynthetic substitution of a porous organic polymer 1 produced the sulfonated solid polymer 1S (see scheme), which exhibited a remarkable conductivity of 7.72×10⁻² S cm⁻¹ at 80 °C and 90 % relative humidity. The sulfonated material also revealed long-term performance over more than 3 months without conductivity decay, and its cost-effective synthesis is scalable for mass production.

Atom by atom, aberration-corrected scanning transmission electron microscopy has revealed the atomic positions of light elements within the porous titanosilicate network ETS-10. The ion-exchange capability of ETS-10 with respect to rare earth cations was also investigated.

Safer, greener, stronger: Trinitropyrazoles are a powerful class of energetic materials. The connection of two nitropyrazole rings by a methylene bridge afforded three energetic compounds (see picture) with high potential as explosives for different applications. Besides the low sensitivity and high thermal stability of the compounds, their high performance was demonstrated by combined theoretical and experimental studies.

Feeling a little strained? The enantioselective (4+2) annulation of donor–acceptor cyclobutanes with unsaturated acyl fluorides using N-heterocyclic carbene (NHC) catalysis has been discovered. The reaction provides a 3-step entry to cyclohexyl β-lactones (25 examples) in excellent chemical yield (most ≥90 %) and stereochemical integrity (all >20:1 d.r., most ≥97:3 e.r.).

An isolable cyclic silylene stabilized by two different strongly π-donating groups, an amino group and a phosphonium ylide, was synthesized. The combination of these two π-donating substituents confers high thermal stability and strong nucleophilic character on the silylene. Its electron-donating character is comparable to that of NHC ligands, despite the fact that stable silylenes have been thought to be more weakly donating than phosphines.

The green(air), the better! Moving closer to the dream of hydrous/aerobic organolithium chemistry, replacing toxic organic solvents by green and biorenewable deep eutectic solvents (DESs) enables regioselective addition of organolithium reagents to non-activated imines at room temperature in air.

Adding value to natural gas: A hydrogen-permeable tubular ceramic membrane reactor was developed, enabling Fe©SiO₂-catalyzed CH₄ upgrading to higher hydrocarbons. The Fe©SiO₂ catalyst demonstrated a stable 30 % C₂₊ single-pass yield, with up to 30 % CH₄ conversion and 99 % selectivity to C₂ and aromatic products.

Targeting complexity: A unique combination of organocatalysis with lanthanide catalysis directly leads to complex tricyclic structures from readily available and simple compounds. Six new bonds and six stereocenters are formed with virtually complete stereoselectivity in this multicomponent one-pot procedure. fod=2,2-dimethyl-6,6,7,7,8,8,8-heptafluorooctane-3,5-dionato.

Tris(pentafluoroethyl)silane was used for hydrosilylation reactions. It can be deprotonated by sterically demanding bases at low temperatures, which leads to the formation of the corresponding silanide ion. Addition of crown ethers or cryptands allows the isolation and characterization of the salt-like tris(pentafluoroethyl)silanide at room temperature. Interception of the silanide with Pt^IICl₂ resulted in the formation of a silyl-substituted platinum complex.

Easily transferred: The tris(pentafluoroethyl)silanide anion is accessible by the deprotonation of Si(C₂F₅)₃H at low temperatures. Subsequent quenching with suitable electrophiles leads to a plethora of tris(pentafluoroethyl)silane derivatives and underlines the versatility of Li[Si(C₂F₅)₃] as a powerful nucleophilic transfer reagent of the [Si(C₂F₅)₃]⁻ unit.

Where is the n-d? The connection of sulfate tetrahedra leads to polysulfate chains according to [S_nO_3n+1]²⁻ and brings up the question how long the chains might be? The structural details of the new hexasulfate anion [S₆O₁₉]²⁻ anion and theoretical investigations on such polysulfate anions seems to answer the question: The end is probably reached.

Insights in solution: NMR spectroscopy reveals a unique, non-native structure of a monomeric transthyretin protein that carries the clinically important T119M mutation and thereby suggests a mechanism that contributes to protection from amyloid disease.

On target: Cytoplasmic re-targeting of the most widely used eukaryotic genetic code expansion machinery substantially increases the residue-specific incorporation of noncanonical amino acids into proteins in mammalian cells. This approach can be combined with ultrafast Diels–Alder click reactions for DNA-PAINT-based super-resolution microscopy. The “Click-PAINT” system enables high-contrast, residue-specific imaging of even low-abundance proteins.