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Molecular glue compounds induce protein–protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation 1 . Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets 2 . They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Here, through systematically mining databases for correlations between the cytotoxicity of 4,518 clinical and preclinical small molecules and the expression levels of E3 ligase components across hundreds of human cancer cell lines 3 – 5 , we identify CR8—a cyclin-dependent kinase (CDK) inhibitor 6 —as a compound that acts as a molecular glue degrader. The CDK-bound form of CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12–cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy through which target-binding molecules could be converted into molecular glues. The cyclin-dependent kinase inhibitor CR8 acts as a molecular glue compound by inducing the formation of a complex between CDK12–cyclin K and DDB1, which results in the ubiquitination and degradation of cyclin K.

This study deals with the scanning electron microscopy (SEM) analyses of the phase interfaces in the glued joints between Norway spruce wood elements thermally modified at 160, 180, 200, and 220 °C/4 h and polyurethane (PUR) and polyvinyl acetate (PVAc) glues with the aim of evaluating various anatomical influences of wood on the quality of joints. Due to cracked regions created in the surface of spruce wood at severe thermal modifications, the penetration depth of glues doubled from 140 to 241 μm for PUR glue, and from 100 to 200 μm for PVAc glue. The thickness of glue lines in joints was apparently higher for PVAc glue, mainly in earlywood regions; however, in joints from thermally modified (TM) woods it increased more apparently for PUR glue from 16.6 to 44.4 μm, probably in connection with formation of micro-bubbles in its structure. The SEM analyses corresponded well with the previous knowledge about lower shear strength of glued joints formed from the more intensively TM spruce elements and mentioned types of glues.

Nanoparticles-based glues have recently been shown with substantial potential for hydrogel adhesion. Nevertheless, the transformative advance in hydrogel-based application places great challenges on the rapidity, robustness, and universality of achieving hydrogel adhesion, which are rarely accommodated by existing nanoparticles-based glues. Herein, we design a type of nanohesives based on the modulation of hydrogel mechanics and the surface chemical activation of nanoparticles. The nanohesives can form robust hydrogel adhesion in seconds, to the surface of arbitrary engineering solids and biological tissues without any surface pre-treatments. A representative application of hydrogel machine demonstrates the tough and compliant adhesion between dynamic tissues and sensors via nanohesives, guaranteeing accurate and stable blood flow monitoring in vivo. Combined with their biocompatibility and inherent antimicrobial properties, the nanohesives provide a promising strategy in the field of hydrogel based engineering. Achieving rapid, robust, and universal hydrogel adhesion poses challenges for nanoparticle-based glues. Here, the authors present nanohesives that can adhere to diverse surfaces without pre-treatment based on hydrogel mechanics design and interface chemistry modification.

Growing urban populations and deteriorating infrastructure are driving unprecedented demands for concrete, a material for which there is no alternative that can meet its functional capacity. The production of concrete, more particularly the hydraulic cement that glues the material together, is one of the world’s largest sources of greenhouse gas (GHG) emissions. While this is a well-studied source of emissions, the consequences of efficient structural design decisions on mitigating these emissions are not yet well known. Here, we show that a combination of manufacturing and engineering decisions have the potential to reduce over 76% of the GHG emissions from cement and concrete production, equivalent to 3.6 Gt CO 2 -eq lower emissions in 2100. The studied methods similarly result in more efficient utilization of resources by lowering cement demand by up to 65%, leading to an expected reduction in all other environmental burdens. These findings show that the flexibility within current concrete design approaches can contribute to climate mitigation without requiring heavy capital investment in alternative manufacturing methods or alternative materials. This work quantifies the climate benefits of efficiently utilizing concrete through improved material and structural design, and it shows that over 75% of CO2 emissions from global concrete production could be cut with already implementable measures

Mammalian development demands precision. Millions of molecules must be properly located in temporal order, and their function regulated, to orchestrate important steps in cell cycle progression, apoptosis, migration and differentiation, to shape developing embryos. Ubiquitin and its associated enzymes act as cellular guardians to ensure precise spatio-temporal control of key molecules during each of these important cellular processes. Loss of precision results in numerous examples of embryological disorders or even cancer. This Review discusses the crucial roles of E3 ubiquitin ligases during key steps of early mammalian development and their roles in human disease, and considers how new methods to manipulate and exploit the ubiquitin regulatory machinery — for example, the development of molecular glues and PROTACs — might facilitate clinical therapy.E3 ubiquitin ligases ensure the precise spatiotemporal control of key molecules during important cellular processes. This Review discusses the crucial roles of E3 ligases during early mammalian development and their roles in human disease, and considers how new methods to manipulate the ubiquitin regulatory machinery — for example, the development of molecular glues and PROTACs — might facilitate clinical therapy.

Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)—bifunctional compounds composed of two separate moieties that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target 1 – 4 . Here, using orthogonal genetic screening, biophysical characterization and structural reconstitution, we investigate the mechanism of action of bifunctional degraders of BRD2 and BRD4, termed intramolecular bivalent glues (IBGs), and find that instead of connecting target and ligase in trans as PROTACs do, they simultaneously engage and connect two adjacent domains of the target protein in cis . This conformational change ‘glues’ BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target–ligase affinities that do not translate to BRD4 degradation in the absence of compound. Structural insights into the ternary BRD4–IBG1–DCAF16 complex guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, which works by bridging protein domains in cis to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation. Studies using genetic screening, biophysical characterization and structural reconstitution elucidate the mechanism of action and enable rational design of a new class of functional compounds that glue target proteins to E3 ligases via intramolecularly bridging two domains to enhance intrinsic protein–protein interactions and promote target ubiquitination and degradation.

The ability to control nanostructure shape and dimensions presents opportunities to design materials in which their macroscopic properties are dependent upon the nature of the nanoparticle. Although particle morphology has been recognized as a crucial parameter, the exploitation of the potential shape-dependent properties has, to date, been limited. Herein, we demonstrate that nanoparticle shape is a critical consideration in the determination of nanocomposite hydrogel properties. Using translationally relevant calcium-alginate hydrogels, we show that the use of poly( L -lactide)-based nanoparticles with platelet morphology as an adhesive results in a significant enhancement of adhesion over nanoparticle glues comprised of spherical or cylindrical micelles. Furthermore, gel nanocomposites containing platelets showed an enhanced resistance to breaking under strain compared to their spherical and cylindrical counterparts. This study opens the doors to a change in direction in the field of gel nanocomposites, where nanoparticle shape plays an important role in tuning mechanical properties. The ability to control nanostructure shape and dimensions presents opportunities to design materials in which their macroscopic properties are dependent upon the nature of the nanoparticle. Here the authors show nanoparticle shape is a critical consideration in the determination of nanocomposite hydrogel properties.

The development of biomedical glues is an important, yet challenging task as seemingly mutually exclusive properties need to be combined in one material, i.e. strong adhesion and adaption to remodeling processes in healing tissue. Here, we report a biocompatible and biodegradable protein-based adhesive with high adhesion strengths. The maximum strength reaches 16.5 ± 2.2 MPa on hard substrates, which is comparable to that of commercial cyanoacrylate superglue and higher than other protein-based adhesives by at least one order of magnitude. Moreover, the strong adhesion on soft tissues qualifies the adhesive as biomedical glue outperforming some commercial products. Robust mechanical properties are realized without covalent bond formation during the adhesion process. A complex consisting of cationic supercharged polypeptides and anionic aromatic surfactants with lysine to surfactant molar ratio of 1:0.9 is driven by multiple supramolecular interactions enabling such strong adhesion. We demonstrate the glue’s robust performance in vitro and in vivo for cosmetic and hemostasis applications and accelerated wound healing by comparison to surgical wound closures. Biomedical glues often face a challenge in providing strong adhesion and providing remodelling capabilities. Here the authors report on the development of a biocompatible and biodegradable protein-based coacervate adhesive and demonstrate application in haemostasis and wound healing using pig models.