Abstract Molecular glues are opening up new therapeutic areas by turning previously undruggable and intractable proteins into tractable targets through the formation or stabilisation of a ternary complex between two proteins. The present review focuses on how such structures are obtained and leveraged to guide rational design. Ternary complexes can be classified by protein–protein interface architecture and degree of topological constraint, informing the design process towards a given biological outcome. As with conventional small-molecule drug discovery, structural information provides invaluable insights for rational optimisation of glues, but solving a ternary complex structure remains a significant challenge owing to the underlying three-body equilibrium. Biophysical characterisation of cooperativity and ternary complex half-life not only provides optimisation parameters but also provides a means for prioritising the most promising glues for ternary structural studies by X-ray crystallography or cryogenic electron microscopy. Once solved, a ternary structure enables conventional structure-based design, such as scaffold hopping and surface decoration, and increasingly informs computational methods, though these remain most powerful when grounded in experimental validation. Ternary complex structures for canonical glue systems are now available in relative abundance, providing a foundation for both empirical and computational design; expanding this coverage beyond well-studied glue receptors and binding partners will test how broadly these principles generalise.
The study of bacterial sociality, understanding when and how bacteria interact and the consequences of those interactions, has rapidly grown in popularity over the last 20 years. This has revealed that bacteria engage in a remarkable variety of social interactions, including complex cell-cell communication, the exchange of an arsenal of inhibitory molecules, and the sharing of metabolites. These interactions can have significant consequences for the host or environment they reside in, and numerous mechanisms of interaction have attracted significant interest for their therapeutic potential. The present special issue contains eight review articles addressing three major questions in bacterial sociality (Who is where? How are they interacting? And what are the implications of this?) alongside five methods-focused articles that introduce some particularly valuable approaches for the study of bacterial interactions.
Although the study of microbes started with type strains and reference genomes, advances in sequencing technology and new interest in mixed microbial communities have made us aware that a single genome cannot and does not reflect the diversity of a given bacterial species. Bacteria rarely occupy an environmental or host niche alone and quickly diversify into strains upon colonization of a new niche. The genetic diversity present within a phylogenetically related set of bacterial strains (the 'pangenome') is influenced by the niche that they occupy and how they interact with the other microorganisms that they share that niche with. In this review, I examine how the social lives of bacteria can affect their genetic diversity and the bioinformatic techniques that we use to detect that diversity.
The spatial organization of microbiomes illuminates their structure, function, and relationship to their host. Using fluorescence spectral imaging to discriminate up to 16 fluorophores and using combinations of probes to generate unique spectral signatures, combinatorial labeling and spectral imaging-fluorescence in situ hybridization (CLASI-FISH) has been deployed to analyze spatial organization in oral, gut, and marine microbiomes. In dental plaque, imaging revealed the structural role of Corynebacterium matruchotii in organizing the plaque biofilm and revealed previously unrecognized complexity in dental plaque corncob structures. Tongue dorsum biofilms showed a patchy organization around a core of host epithelial cells projecting from the tongue surface, with anaerobes located near the core and oxygen-tolerant taxa near the surface. Taxa that are prominent in these tongue dorsum communities can reduce nitrate to nitrite and thus may play an important role in human nitrate metabolism. In contrast with the highly structured organization of oral biofilms, analysis of the gut microbiome by CLASI-FISH showed a mixed community, indicating that the rate of mixing in the gut is high enough to overcome the tendency of bacterial replication to generate single-taxon patches. Application of CLASI-FISH to blades of kelp showed a dense biofilm with clusters of cocci near the kelp surface, bacteria invading the kelp tissue, and rod-shaped and filamentous bacteria extending into the water column. Collectively, visualizing the spatial organization of host-associated microbiomes reveals spatial relationships among taxa and between microbes and host and serves to generate predictions about the dynamics of the host-microbiome interaction.
Alzheimer's disease (AD) is a complex neurodegenerative disorder involving amyloid-β deposition, tau aggregation, neuroinflammation, synaptic dysfunction, and microvascular and epigenetic changes. Although recent therapeutic developments have energised the field, effective and widely accessible disease-modifying treatments remain limited. This reflects both the biological complexity of AD and the continuing challenge of validating drug targets in the central nervous system (CNS). Chemical probes are small molecules designed to investigate the function of specific proteins in biological systems. When selected and used carefully, they provide powerful tools for testing how particular targets and pathways contribute to AD biology. High-quality chemical probes for AD targets must have high selectivity, confirmed target engagement, and CNS exposure adequate for the specific biological question, with low efflux, and biomarker evidence that the intended target is engaged in brain-relevant tissue. CNS penetration should be interpreted alongside mechanism-appropriate pharmacodynamic biomarkers, since cerebrospinal fluid measurements and modelled Kp,uu do not always directly reflect brain exposure. Chemical probes have shaped current understanding of major AD-relevant pathways, including amyloid precursor protein processing by BACE1 and γ-secretase, tau phosphorylation and aggregation, epigenetic regulation, and neuroinflammatory signalling. Several compounds initially developed as potential therapies have provided valuable mechanistic insight, even where they did not translate into clinical benefit. New modalities, including targeted protein degradation, molecular glues, and peptides, are expanding the range of AD biology that can be studied. These developments illustrate the value and limitations of chemical probes and underline the need for rigorous probe selection, validation, and experimental design in AD research.
