Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound , a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein-ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound is a<3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4-11 cells with an IC of 3 μM after 6 h.
CO2 electrochemical reduction (CO2RR) can mitigate environmental issues while providing valuable products, yet challenging in activity, selectivity, and stability. Here, a CuS‐Bi2S3 heterojunction precursor is reported that can in situ reconstruct to Cu‐doped Bismuth (CDB) electrocatalyst during CO2RR. The CDB exhibits an industrial‐compatible current density of −1.1 A cm−2 and a record‐high formate formation rate of 21.0 mmol h−1 cm−2 at −0.86 V versus the reversible hydrogen electrode toward CO2RR to formate, dramatically outperforming currently reported catalysts. Importantly, the ultrawide potential region of 1050 mV with high formate Faradaic efficiency of over 90% and superior long‐term stability for more than 100 h at −400 mA cm−2 can also be realized. Experimental and theoretical studies reveal that the remarkable CO2RR performance of CDB results from the doping effect of Cu which optimizes adsorption of the *OCHO and boosts the structural stability of metallic bismuth catalyst. This study provides valuable inspiration for the design of element‐doping electrocatalysts to enhance catalytic activity and durability.
The intrinsic sluggish kinetics of the oxygen evolution reaction (OER) limit the improvement of hydrogen evolution reaction (HER) performance, and substituting the anodic oxidation of biomass materials is an alternative approach, given its lower oxidation potential and higher added value compared to those of OER. In this study, a Ni3S2‐MoS2 nanoheterojunction catalyst with strong electronic interactions is prepared. It exhibits high efficiency for both the HER and the electrooxidation of 5‐hydroxymethylfurfural (HMF). In a two‐electrode cell with Ni3S2‐MoS2 serving as both the anode and cathode, the potential is only 1.44 V at a current density of 10 mA cm−2, which is much lower than that of pure water splitting. Density functional theory calculations confirm that the strong chemisorption of H and HMF at the interface leads to outstanding electrocatalytic activity. The findings not only provide a strategy for developing efficient electrocatalysts, but also provide an approach for the continuous production of high value‐added products and H2.
For tandem reactions with several
intermediate products, improving
the reaction rate of each step is vital for accelerating the entire
reaction. However, simultaneously enhancing the conversions of different
intermediates using a single-active-site catalyst remains a challenge
because the catalyst commonly promotes only one type of reaction.
Herein, a Co-based double-active-site relay catalyst (denoted as (Co1→Cop)/N-CNTs) is reported. Due to the preferable
catalytic activities of Co single atoms (Co1) and Co nanoparticles
(Cop) for the oxidation of hydroxyls to aldehyde groups
and aldehydes to carboxyl groups, respectively, the prepared (Co1→Cop)/N-CNTs exhibited good catalytic performance
for the aerobic oxidation of 5-hydroxymethylfurfural (HMF) to 2,5-furandicarboxylic
acid (FDCA). The catalyst achieved 100% HMF conversion efficiency
and 96% FDCA yield under a 0.1 MPa O2 atmosphere at 100
°C for 8 h. The presented strategy offers prospects for the development
of highly active catalysts for complex tandem reactions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.