Although conventional genetic modification approaches for protein knockdown work very successfully due to the increasing use of CRISPR/Cas9, effective techniques for achieving protein depletion in adult animals, especially in large animals such as non-human primates, are lacking. Here, we report a chemical approach based on PROTACs technology that efficiently and quickly knocks down FKBP12 (12-kDa FK506-binding) protein globally in vivo. Both intraperitoneal and oral administration led to rapid, robust, and reversible FKBP12 degradation in mice. The efficiency and practicality of this method were successfully demonstrated in both large and small animals (mice, rats, Bama pigs, and rhesus monkeys). Furthermore, we showed this approach can also be applied to effectively knockdown other target proteins such as Bruton's tyrosine kinase (BTK). This chemical protein knockdown strategy provides a powerful research tool for gene function studies in animals, particularly in large animals, for which gene-targeted knockout strategies may remain unfeasible.
Viral infections are increasing and probably long-lasting global risks. In this study, a chemical library was exploited by phenotypic screening to discover new antiviral inhibitors. After optimizations from hit to lead, a novel potent small molecule (RYL-634) was identified, showing excellent broad-spectrum inhibition activity against various pathogenic viruses, including hepatitis C virus, dengue virus, Zika virus, chikungunya virus, enterovirus 71, human immunodeficiency virus, respiratory syncytial virus, and others. The mechanism of action and potential targets of RYL-634 were further explored by the combination of activity-based protein profiling and other techniques. Finally, human dihydroorotate dehydrogenase was validated as the major target of RYL-634. We did not observe any mutant resistance under our pressure selections with RYL-634, and it had a strong synergistic effect with some Food and Drug Administration-approved drugs. Hence, there is great potential for developing new broad-spectrum antivirals based on RYL-634.
A novel palladium catalyzed hydroxylation of unactivated aliphatic C(sp(3))-H bonds was successfully developed. Different from conventional methods, water serves as the hydroxyl group source in the reaction. This new reaction demonstrates good reactivity and broad functional group tolerance. The C-H hydroxylated products can be readily transformed into various highly valuable chemicals via known transformations. Based on experimental and theoretical studies, a mechanism involving the Pd(II)/(IV) pathway is proposed for this hydroxylation reaction.
The development of an efficient method for the construction of biologically relevant sultams is described, which represents the first case of cobalt-promoted C-H/N-H functionalization of sulfonamides with allenes. This newly developed annulation reaction demonstrated good functional group tolerance and excellent regioselectivity. Both terminal monosubstituted allenes and internal disubstituted allenes can be employed to give the desired sultams in good yields. This strategy can be successfully used to build a unique sultam library with novel structural diversity.
The
fundamental obstacle that only a few part of hydrogen energy
is currently produced by industrial electrocatalysis, is in insufficient
performance and high cost of even the most advanced catalysts. To
meet the demand for high-performance, lasting catalysts at industry-relevant
current densities (≥500 mA cm–2) with overpotentials
≤300 mV, here, we uniquely heterointerface the Ni, Co, and
W phosphoxide phases in situ on plasma-defect-engineered Ni–Co
support (M
x
O@M
x
P/PNCF (M = Ni, Co, W) core–shell heterostructure) to dramatically
enhance the electrocatalytic performances with very high current densities.
The achieved H2 evolution requires low overpotentials of
only 53 and 343 mV for current densities of 10 (j
10) and 1000 mA cm–2 (j
1000) and shows fast reaction kinetics with a small Tafel
slope of 40 mV dec–1. Importantly, the M
x
O@M
x
P/PNCF presents
spectacular activity at industry-relevant current densities (>j
300) and outperforms the industry Pt/C benchmark.
Our catalyst shows excellent long-term stability and durability with
no significant activity loss after 104 cycles and 100 h
of operation in an alkaline electrolyte. First-principles simulations
reveal the best metal-phosphide combination to minimize the Gibbs
energy for absorbing H+ ions on the reactive sites and
to enhance the desorption of H2.
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