The
use of peptidomimetic scaffolds is a promising strategy for
the inhibition of protein–protein interactions (PPIs). Herein,
we demonstrate that sulfono-γ-AApeptides can be rationally designed
to mimic the p53 α-helix and inhibit p53–MDM2 PPIs. The
best inhibitor, with K
d and IC50 values of 26 nM and 0.891 μM toward MDM2, respectively, is
among the most potent unnatural peptidomimetic inhibitors disrupting
the p53–MDM2/MDMX interaction. Using fluorescence polarization
assays, circular dichroism, nuclear magnetic resonance spectroscopy,
and computational simulations, we demonstrate that sulfono-γ-AApeptides
adopt helical structures resembling p53 and competitively inhibit
the p53–MDM2 interaction by binding to the hydrophobic cleft
of MDM2. Intriguingly, the stapled sulfono-γ-AApeptides showed
promising cellular activity by enhancing p53 transcriptional activity
and inducing expression of MDM2 and p21. Moreover, sulfono-γ-AApeptides
exhibited remarkable resistance to proteolysis, augmenting their biological
potential. Our results suggest that sulfono-γ-AApeptides are
a new class of unnatural helical foldamers that disrupt PPIs.
Vegetable oil is mainly composed of triacylglycerol (TAG), a storage lipid that serves as a major commodity for food and industrial purposes, as well as an alternative biofuel source. While TAG is typically not produced at significant levels in vegetative tissues, emerging evidence suggests that its accumulation in such tissues may provide one mechanism by which plants cope with abiotic stress. Different types of abiotic stress induce lipid remodeling through the action of specific lipases, which results in various alterations in membrane lipid composition. This response induces the formation of toxic lipid intermediates that cause membrane damage or cell death. However, increased levels of TAG under stress conditions are believed to function, at least in part, as a means of sequestering these toxic lipid intermediates. Moreover, the lipid droplets (LDs) in which TAG is enclosed also function as a subcellular factory to provide binding sites and substrates for the biosynthesis of bioactive compounds that protect against insects and fungi. Though our knowledge concerning the role of TAG in stress tolerance is expanding, many gaps in our understanding of the mechanisms driving these processes are still evident. In this review, we highlight progress that has been made to decipher the role of TAG in plant stress response, and we discuss possible ways in which this information could be utilized to improve crops in the future.
Visible
light-promoted dearomative [2 + 2] cycloaddition of indole
derivatives tethered with olefins at the N1 position has been considered
thermodynamically unfeasible due to the high triplet excited-state
energies. We describe visible light-promoted [2 + 2] cycloaddition
with concomitant dearomatization of indole derivatives tethered with
olefins at the N1 position via the energy transfer process, providing
cyclobutane-fused polycyclic indoline derivatives that are potentially
useful in drug design and discovery. These cyclobutane-fused indoline-based
polycycles are obtained in high yields and with good diastereoselectivities
(>99:1). The key to the success of the reaction is the formation
of
H-bond(s) between N-alkenoylindole and solvent, enabling
the reduction of the triplet energy of the indole derivatives, which
greatly improved the efficiency of the protocol. The applicability
of the method is demonstrated by late-stage skeletal diversification
of indole-containing bioactive molecules, which provides a powerful
strategy for the rapid skeleton remodeling. DFT calculations were
used to give a deep understanding of the reaction pathways.
Background
Nano-drug delivery systems show considerable promise for effective cancer therapy. Polymeric micelles have attracted extensive attention as practical nanocarriers for target drug delivery and controlled drug delivery system, however, the distribution of micelles and the release of the drug are difficult to trace in cancer cells. Therefore, the construction of a redox-sensitive multifunctional drug delivery system for intelligent release of anticancer drugs and simultaneous diagnostic imaging and therapy remains an attractive research subject.
Results
To construct a smart drug delivery system for simultaneous imaging and cancer chemotherapy, mPEG-ss-Tripp was prepared and self-assembled into redox-sensitive polymeric micelles with a diameter of 105 nm that were easily detected within cells using confocal laser scanning microscopy based on aggregation-induced emission. Doxorubicin-loaded micelles rapidly released the drug intracellularly when GSH reduced the disulfide bond. The drug-loaded micelles inhibited tumor xenografts in mice, while this efficacy was lower without the GSH-responsive disulfide bridge. These results establish an innovative multi-functional polymeric micelle for intracellular imaging and redox-triggered drug deliver to cancer cells.
Conclusions
A novel redox-sensitive drug delivery system with AIE property was constructed for simultaneous cellular imaging and intelligent drug delivery and release. This smart drug delivery system opens up new possibilities for multifunctional drug delivery systems.
Novel
unprecedented helical foldamers have been effectively designed and
synthesized. The homogeneous right-handed d-sulfono-γ-AApeptides
represent a new generation of unnatural helical peptidomimetics, which
have similar folding conformation to α-peptides, making them
an ideal molecular scaffold to design α-helical mimetics. As
demonstrated with p53-MDM2 PPI as a model application, the right-handed d-sulfono-γ-AApeptides reveal much-enhanced binding affinity
compared to the p53 peptide. The design of d-sulfono-γ-AApeptides
may provide a new and alternative strategy to modulate protein–protein
interactions.
Peptidomimetics
have gained great attention for their function
as protein–protein interaction (PPI) inhibitors. Herein, we
report the design and investigation of a series of right-handed helical
heterogeneous 1:1 α/Sulfono-γ-AA peptides as unprecedented
inhibitors for p53-MDM2 and p53-MDMX. The most potent helical heterogeneous
1:1 α/Sulfono-γ-AA peptides were shown to bind tightly
to MDM2 and MDMX, with K
d of 19.3 and
66.8 nM, respectively. Circular dichroism spectra, 2D-NMR spectroscopy,
and the computational simulations suggested that these helical sulfono-γ-AA
peptides could mimic the critical side chains of p53 and disrupt p53/MDM2
PPI effectively. It was noted that these 1:1 α/Sulfono-γ-AA
peptides were completely resistant to proteolytic degradation, boosting
their potential for biomedical applications. Furthermore, effective
cellular activity is achieved by the stapled 1:1 α/Sulfono-γ-AA
peptides, evidenced by significantly enhanced p53 transcriptional
activity and much more induced level of MDM2 and p21. The 1:1 α/Sulfono-γ-AA
peptides could be an alternative strategy to antagonize a myriad of
PPIs.
B(C6F5)3-catalyzed deoxygenation of ether-substituted alcohols and carbonyl compounds has been developed using (HMe2SiCH2)2 as the reductant. This unique reagent shows distinct superiority over traditional one silicon-centered hydrosilanes, giving the corresponding alkanes in high yields with good tolerance of ethers, aryl halides and alkenes. The control experiments suggest that (HMe2SiCH2)2 might facilitate the approach in an intramolecular Si/O activation manner.
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