Articles in 2023

The design and construction of a stereo-defined DNA-encoded chemical library, featuring the four different 4-amino-proline stereoisomers as a central scaffold, has now enabled the discovery of potent ligands to proteins of pharmaceutical interest. Parallel screening with closely related isoforms (anti-targets) facilitated the isolation of hits with high selectivity ratios.

An enzymatic reaction installs endogenous β-amino acids in proteins with unique reactivity. Now it has been shows that this reaction can be used for site-specific modification with tetrazine dienophiles to introduce labels onto target proteins. Applications include generation of a radiolabel chelator-modified Her2-binding Affibody and intracellular, fluorescently labelled cell division protein FtsZ.

Inspired by the design of peptide and nucleic acid sequences to adopt particular three-dimensional shapes, natural glycan motifs have now been combined to construct a glycan that adopts a hairpin conformation in water. Thus a designed glycan can now autonomously fold into a stable secondary structure absent in nature.

Aluminium and silicon, two Earth-abundant, well-understood elements, typically form weak Al–Si bonds. Now, complexes featuring an anionic Al–Si core stabilized by bulky substituents and a Si–Na interaction have been isolated. This Al–Si interaction possesses partial double bond character, which can be increased by sequestration of the sodium counterion.

Microtubules carry patterns of post-translational modifications that are important for the regulation of key cellular processes. Now a semi-synthetic method facilitates the production of tubulins with defined post-translational modifications. Using these designer tubulins, polyglutamylation of α-tubulin is found to promote its detyrosination by enhancing the activity of the carboxypeptidase vasohibin/small vasohibin-binding protein.

Visualizing single-molecule reactions using electron microscopy can be difficult because of potential radiation damage from the electron beam. Now, however, it has been shown that a high-energy electron beam can be used to synthesize metallo-azafullerenes. Atomic-resolution, time-resolved transmission electron microscopy, with the help of computational calculations, is used to monitor the metal-encapsulation dynamics.

Celastrol is a potent anti-obesity agent found in the root of Tripterygium wilfordii, but its medicinal application is compromised by limited availability. Now, by combining plant biochemistry with metabolic engineering and chemistry, the biosynthetic pathway of celastrol has been elucidated and has afforded its scalable production in yeast.

The morphan core is central to strychnan alkaloid synthesis and is typically formed during the middle or later stages of the process. Now it has been shown that an allene/ketone-equipped morphan core can be constructed early in the synthesis through ketone α-allenylation and then used to introduce other rings and functionalities, enabling access to nine targets including strychnine and geissolosimine.

There is currently a lack of effective synthetic strategies for combining lactams and pyridines within a single molecular structure. Now, diastereoselective pyridyl lactamization has been developed using a photoinduced [3+2] cycloaddition of triplet diradical N–N pyridinium ylides with pendant alkenes. This method provides a useful synthon for preparing pyridyl γ- and δ-lactam scaffolds with syn-configuration.

Stabilization of RNAs for storage, transport and biological application remains a profound challenge. Now, it has been shown that reversible 2′-OH acylation with easily accessible acylimidazoles unlocks efficient protection of RNA. RNA can be deprotected by non-basic nucleophiles or spontaneously in cells to restore RNA functions.

Two glycosylated enzymes, EupfF and PycR1, have now been characterized and shown to independently catalyse the tandem intermolecular [4 + 2] cycloaddition in the biosynthesis of bistropolone-sesquiterpenes. Through analysis of enzyme–substrate co-crystal structures, together with computational and mutational studies, the origins of their catalytic activity and stereoselectivity were elucidated.

Traditionally, ozone has been primarily used to oxidatively deconstruct carbon–carbon bonds. Now, it has been shown that ozone can be used for the construction of carbon–oxygen bonds without oxidative cleavage of the olefin substrate through capturing primary ozonides. Furthermore, intercepting primary ozonides with nucleophiles in continuous flow enabled the green, syn-dihydroxylation of olefins to be realized.

Conventional photo-driven cancer treatment agents require oxygen and visible light to induce cell death, limiting their efficacy in deep, oxygen-poor tumours. Now, a class of NIR-activatable Pt(IV) photooxidants that target the endoplasmic reticulum have been shown to effectively overcome these limitations by directly oxidizing intracellular biomolecules in an oxygen-independent fashion, presenting a promising new direction for next-generation metal-based drug development.

Contrary to agonist binding being the sole driver for β₂-adrenergic receptor (β₂AR) activation, molecular metadynamics simulations now reveal a distinct activation mechanism. Coupling β₂AR with its cognate Gs protein induces considerable structural changes, activating both proteins. Gs opens its GDP binding pocket while β₂AR undergoes expansion.

Large collections of defined glycosaminoglycan (GAG) structures have been synthetically challenging to obtain but are required to understand this important class of biomolecules. Now, an efficient platform for synthesizing large libraries of heparan sulfate oligosaccharides has been developed, providing a detailed view into the sulfation code of GAGs.

Exciton–exciton annihilation is conventionally assumed to be limited by diffusion. Now, using time-resolved photoluminescence microscopy to determine exciton diffusion constants and annihilation rates in two substituted perylene diimide aggregates, along with a microscopic model, it has been shown that annihilation can be suppressed through quantum interference of the spatial phase of delocalized excitons.

The mechanism of α-synuclein amyloid aggregation via liquid–liquid phase separation has so far remained elusive. Now, the existence of nanoscale clusters of α-synuclein in sub-saturated concentrations is observed using mass photometry. These nanoscale clusters can act as precursors to both macroscopic condensate droplets as well as amyloid fibrils.

The covalent capture of a ligand by its target protein(s) is important for drug-target identification. Now an electrochemically active warhead—diazetidinone—can be leveraged in a chemoproteomics platform for electroaffinity labelling of a ligand’s target protein to afford target-ligand identification in live cells.

Fluorescent sensors that are responsive only in a specific subcellular location have remained elusive. Now, a chemogenetic sensing platform has been developed to sense glutathione in a user-defined organelle of interest. These tools enable quantitative studies of subcellular glutathione homeostasis using visible or near-infrared wavelengths.

Mutually orthogonal aminoacyl transfer RNA synthetase/transfer RNA pairs are required for genetically encoding non-canonical amino acids into proteins, as well as for the encoded cellular synthesis of polymers and macrocycles; however, the scalable discovery of such pairs is challenging. A quintuply orthogonal set of pyrrolysyl-tRNA synthetase/pyrrolysyl-tRNA pairs has now been generated through tRNA screening, engineering and directed evolution.