Light-driven thermocatalytic CO2 reduction by CH4 on alumina-cluster-modified Ni nanoparticles with excellent durability and high light-to-fuel efficiency promoted by the photoactivation effect.

Using inexhaustible solar energy to drive efficient light-driven thermocatalytic CO2 reduction by CH4 (DRM) is an attractive approach that can synchronously reduce the greenhouse effect and convert solar energy into fuels. However, it is often limited by the intense light intensity required to produce high fuel production rates, and the catalyst deactivation due to severe carbon deposition generated from side reactions. Herein, a nanostructure of alumina-cluster-modified Ni nanoparticles supported on Al2O3 nanorods (ACM-Ni/Al2O3) was synthesized, displaying good catalytic performance under focused UV-vis-IR illumination. By light-driven thermocatalytic DRM on ACM-Ni/Al2O3 at a reduced light intensity of 76.9 kW m-2, the high fuel production rates of H2 (rH2, 65.7 mmol g-1 min-1) and CO (rCO, 78.8 mmol g-1 min-1), as well as an efficient light-to-fuel efficiency (η, 26.3 %) are achieved without additional heating. The rH2 and rCO of light-driven thermocatalysis are 2.9 and 1.9 times higher, respectively, compared to conventional thermocatalysis at the same temperature. We have discovered that high light-driven thermocatalytic activity originates from the photoactivation effect, significantly reducing the apparent activation energy and facilitating C* oxidation as a decisive step in DRM. ACM-Ni/Al2O3 possesses excellent durability and exhibits an extremely low coking rate of 4.40 × 10-3 gc gcatalyst-1 h-1, which is 26.8 times lower than that of the reference sample without Al2O3 cluster modification (R-Ni/Al2O3). This is owing to a decrease in activation energies (Ea) of C* oxidation and an increase in Ea of C* polymerization by the surface modification of Ni nanoparticles with Al2O3 clusters, effectively inhibiting carbon deposition.

Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS.

The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. KRAS is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target. We designed a natural product-inspired small molecule that remodels the surface of cyclophilin A (CYPA) to create a neomorphic interface with high affinity and selectivity for the active state of KRASG12C (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRASG12C tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models. This inhibitory strategy can be used to target additional KRAS mutants and other undruggable cancer drivers. Tricomplex inhibitors that selectively target active KRASG12C or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).

A Systematic Approach to the Discovery of Protein-Protein Interaction Stabilizers.

Dysregulation of protein-protein interactions (PPIs) commonly leads to disease. PPI stabilization has only recently been systematically explored for drug discovery despite being a powerful approach to selectively target intrinsically disordered proteins and hub proteins, like 14-3-3, with multiple interaction partners. Disulfide tethering is a site-directed fragment-based drug discovery (FBDD) methodology for identifying reversibly covalent small molecules. We explored the scope of disulfide tethering for the discovery of selective PPI stabilizers (molecular glues) using the hub protein 14-3-3σ. We screened complexes of 14-3-3 with 5 biologically and structurally diverse phosphopeptides derived from the 14-3-3 client proteins ERα, FOXO1, C-RAF, USP8, and SOS1. Stabilizing fragments were found for 4/5 client complexes. Structural elucidation of these complexes revealed the ability of some peptides to conformationally adapt to make productive interactions with the tethered fragments. We validated eight fragment stabilizers, six of which showed selectivity for one phosphopeptide client, and structurally characterized two nonselective hits and four fragments that selectively stabilized C-RAF or FOXO1. The most efficacious fragment increased 14-3-3σ/C-RAF phosphopeptide affinity by 430-fold. Disulfide tethering to the wildtype C38 in 14-3-3σ provided diverse structures for future optimization of 14-3-3/client stabilizers and highlighted a systematic method to discover molecular glues.

Study on the Pyrolysis and Adsorption Behavior of Activated Carbon Derived from Waste Polyester Textiles with Different Metal Salts.

In this study, the effects of the catalysis of heavy metals on the pyrolysis of waste polyester textiles (WPTs) and the adsorption behaviors of the pyrolysis products of WPTs for Cr(VI) were explored. TG-DTG analysis indicated that the metal ions catalyzed the pyrolysis process by reducing the temperature of the decomposition of WPTs. The surface morphology and pore structure of the carbons were analyzed using SEM and BET. The results demonstrated that Zn-AC possessed the largest specific surface area of 847.87 m2/g. The abundant acidic functional groups on the surface of the activated carbons were proved to be involved in the Cr(VI) adsorption process via FTIR analysis. Cr(VI) adsorption experiments indicated that the adsorption process was more favorable at low pH conditions, and the maximum adsorption capacities of Zn-AC, Fe-AC, and Cu-AC for Cr(VI) were 199.07, 136.25, and 84.47 mg/g, respectively. The FTIR and XPS analyses of the carbons after Cr(VI) adsorption, combined with the adsorption kinetics and isotherm simulations, demonstrated that the adsorption mechanism includes pore filling, an electrostatic effect, a reduction reaction, and complexation. This study showed that metal salts catalyze the pyrolysis processes of WPTs, and the activated carbons derived from waste polyester textiles are promising adsorbents for Cr(VI) removal.

Adaptor-Specific Antibody Fragment Inhibitors for the Intracellular Modulation of p97 (VCP) Protein-Protein Interactions.

Protein-protein interactions (PPIs) form complex networks to drive cellular signaling and cellular functions. Precise modulation of a target PPI helps explain the role of the PPI in cellular events and possesses therapeutic potential. For example, valosin-containing protein (VCP/p97) is a hub protein that interacts with more than 30 adaptor proteins involved in various cellular functions. However, the role of each p97 PPI during the relevant cellular event is underexplored. The development of small-molecule PPI modulators remains challenging due to a lack of grooves and pockets in the relatively large PPI interface and the fact that a common binding groove in p97 binds to multiple adaptors. Here, we report an antibody fragment-based modulator for the PPI between p97 and its adaptor protein NSFL1C (p47). We engineered these antibody modulators by phage display against the p97-interacting domain of p47 and minimizing binding to other p97 adaptors. The selected antibody fragment modulators specifically disrupt the intracellular p97/p47 interaction. The potential of this antibody platform to develop PPI inhibitors in therapeutic applications was demonstrated through the inhibition of Golgi reassembly, which requires the p97/p47 interaction. This study presents a unique approach to modulate specific intracellular PPIs using engineered antibody fragments, demonstrating a method to dissect the function of a PPI within a convoluted PPI network.

Interaction Energetics and Druggability of the Protein-Protein Interaction between Kelch-like ECH-Associated Protein 1 (KEAP1) and Nuclear Factor Erythroid 2 Like 2 (Nrf2).

Development of small molecule inhibitors of protein-protein interactions (PPIs) is hampered by our poor understanding of the druggability of PPI target sites. Here, we describe the combined application of alanine-scanning mutagenesis, fragment screening, and FTMap computational hot spot mapping to evaluate the energetics and druggability of the highly charged PPI interface between Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid 2 like 2 (Nrf2), an important drug target. FTMap identifies four binding energy hot spots at the active site. Only two of these are exploited by Nrf2, which alanine scanning of both proteins shows to bind primarily through E79 and E82 interacting with KEAP1 residues S363, R380, R415, R483, and S508. We identify fragment hits and obtain X-ray complex structures for three fragments via crystal soaking using a new crystal form of KEAP1. Combining these results provides a comprehensive and quantitative picture of the origins of binding energy at the interface. Our findings additionally reveal non-native interactions that might be exploited in the design of uncharged synthetic ligands to occupy the same site on KEAP1 that has evolved to bind the highly charged DEETGE binding loop of Nrf2. These include π-stacking with KEAP1 Y525 and interactions at an FTMap-identified hot spot deep in the binding site. Finally, we discuss how the complementary information provided by alanine-scanning mutagenesis, fragment screening, and computational hot spot mapping can be integrated to more comprehensively evaluate PPI druggability.

Modulating protein-protein interaction networks in protein homeostasis.

Protein-protein interactions (PPIs) occur in complex networks. These networks are highly dependent on cellular context and can be extensively altered in disease states such as cancer and viral infection. In recent years, there has been significant progress in developing inhibitors that target individual PPIs either orthosterically (at the interface) or allosterically. These molecules can now be used as tools to dissect PPI networks. Here, we review recent examples that highlight the use of small molecules and engineered proteins to probe PPIs within the complex networks that regulate protein homeostasis. Researchers have discovered multiple mechanisms to modulate PPIs involved in host/viral interactions, deubiquitinases, the ATPase p97/VCP, and HSP70 chaperones. However, few studies have evaluated the effect of such modulators on the target's network or have compared the biological implications of different modulation strategies. Such studies will have an important impact on next generation therapeutics.

Progress towards the broad use of non-peptide synthetic macrocycles in drug discovery.

We discuss progress towards addressing three key questions pertaining to the design of screening libraries of synthetic non-peptidic macrocycles (MCs) for drug discovery: What structural and physicochemical properties of MCs maximize the likelihood of achieving strong and specific binding to protein targets? What features render a protein target suitable for binding MCs, and can this information be used to identify suitable targets for inhibition by MCs? What properties of synthetic MCs confer good pharmaceutical properties, and particularly good aqueous solubility coupled with passive membrane permeability? We additionally discuss how the criteria that define a meaningful MC screening hit are linked to the size of the screening library and the synthetic methodology employed in its preparation.

Quantifying the chameleonic properties of macrocycles and other high-molecular-weight drugs.

Key to the pharmaceutical utility of certain macrocyclic drugs is a 'chameleonic' ability to change their conformation to expose polar groups in aqueous solution, but bury them when traversing lipid membranes. Based on analysis of the structures of 20 macrocyclic compounds that are approved oral drugs, we propose that good solubility requires a topological polar surface area (TPSA, in Å(2)) of ≥0.2×molecular weight (MW). Meanwhile, good passive membrane permeability requires a molecular (i.e., 3D) PSA in nonpolar environments of ≤140Å(2). We show that one or other of these limits is almost invariably violated for compounds with MW>600Da, suggesting that some degree of chameleonic behavior is required for most high MW oral drugs.

Platinum-modulated cobalt nanocatalysts for low-temperature aqueous-phase Fischer-Tropsch synthesis.

Fischer-Tropsch synthesis (FTS) is an important catalytic process for liquid fuel generation, which converts coal/shale gas/biomass-derived syngas (a mixture of CO and H2) to oil. While FTS is thermodynamically favored at low temperature, it is desirable to develop a new catalytic system that could allow working at a relatively low reaction temperature. In this article, we present a one-step hydrogenation-reduction route for the synthesis of Pt-Co nanoparticles (NPs) which were found to be excellent catalysts for aqueous-phase FTS at 433 K. Coupling with atomic-resolution scanning transmission electron microscopy (STEM) and theoretical calculations, the outstanding activity is rationalized by the formation of Co overlayer structures on Pt NPs or Pt-Co alloy NPs. The improved energetics and kinetics from the change of the transition states imposed by the lattice mismatch between the two metals are concluded to be the key factors responsible for the dramatically improved FTS performance.