We
report a facile thiol-yne type reaction triggered by the sulfonium
center. After facile propargylation of thiolethers, the resulting
sulfonium could undergo facile addition with thiols in aqueous media
at ambient temperature. Further applying this reaction in unprotected
peptides bearing neighboring methionine and cysteine could enable
a facile intramolecular addition to construct cyclic peptides with
better stability, good glutathione resistance, and increased cellular
uptakes. Also, the propargylated sulfonium may be used as robust and
versatile probes to target cysteines containing biomolecules.
The
development of bifunction al molecules, which can
enable targeted
RNA degradation, targeted protein acetylation, or targeted protein
degradation, remains a time-consuming process that requires tedious
optimization. We propose a split-and-mix nanoplatform that serves
as a self-adjustable platform capable of facile screening, programmable
ligand ratios, self-optimized biomolecule spatial recognition, and
multifunctional applications. Herein, we demonstrate the potential
of our proposed nanoplatform by showcasing proteolysis-targeting chimeras
(PROTACs), namely, split-and-mix PROTAC (SM-PROTAC). We highlight
the scope of our platform through the targeted disruption of intracellular
therapeutic targets involving ERα, CDK4/6, AR, MEK1/2, BRD2/4,
BCR-ABL, etc. These studies confirm the effectiveness and universality
of the SM-PROTAC platform for proximity-induced applications. This
platform is programmable, with significant potential applications
to biomolecule regulation, including the fields of epigenetics, gene
editing, and biomolecule modification regulation.
A novel
amidation strategy using electrophilic sulfonium, which
is soluble and stable in aqueous conditions, was developed. The sulfoniums
could activate thioacid and carboxyl acid to efficiently react with
amines to afford amides. This method enables applications in amidation
in both aqueous media and solid-phase peptide synthesis, peptide/protein
modifications, and reactive lysines of a proteome at pH 10 with activity-based
protein profiling. A peptide ligand-directed labeling of the USP7–UBL2
domain was also performed using this method.
Peptide-based neoantigen vaccines hold tremendous potential
for
personalized tumor immunotherapy. However, effective delivery and
controllable release of antigen peptides remain major challenges in
stimulating robust and sustained immune responses. Programmable DNA
nanodevices provide accurate fixed positions for antigens, which are
convenient for the calculation of clinical dosage, and hold great
potential as precise carriers. Here, a peptide–nucleic acid
conjugate was prepared, which was driven by a propargyl sulfonium-based
efficient and reversible bio-orthogonal reaction under weakly alkaline
conditions, and folded into regular DNA nanodevice vaccines. The well-defined
nanoplatform not only exhibits outstanding stability in serum, satisfactory
safety, and effective internalization by antigen-presenting cells
(RAW264.7 and BMDCs) but also obviously enhances cytokine (TNF-α,
IL-6, and IL-12) secretion for further immune response. In
vivo, the nanovaccine cooperating with OVA model antigens
and CpG adjuvants stimulated an antigen-specific CD8+T
cell response, significantly preventing the lung metastases of melanoma.
In the B16-OVA tumor-bearing model, the growth inhibition rate of
melanoma reached up to 50%. Similarly, the DNA nanodevice with neoantigen
induced up to a maximum degree of complete MC-38 tumor regression
in 80% of mice, possibly owing to antigen peptide reversible release
driven by sulfonium and further cross-presentation. In brief, this
study demonstrates that DNA nanodevices with sulfonium centers can
provide a precise, biocompatible, and effective co-delivery vaccine
platform for tumor immunotherapy and prevention.
Peptide self-assembly inspired by natural superhelical coiled coils has been actively pursued but remains challenging due to limited helicity of short peptides. Side chain stapling can strengthen short helices but is unexplored in design of self-assembled helical nanofibers as it is unknown how staples could be adapted to coiled coil architecture. Here, we demonstrate the feasibility of this design for pentapeptides using a computational method capable of predicting helicity and fiber-forming tendency of stapled peptides containing noncoded amino acids. Experiments showed that the best candidates, which carried an aromatically substituted staple and phenylalanine analogs, displayed exceptional helicity and assembled into nanofibers via specific head-to-tail hydrogen bonding and packing between staple and noncoded side chains. The fibers exhibited sheet-of-helix structures resembling the recently found collapsed coiled coils whose formation was sensitive to side chain flexibility. This study expands the chemical space of coiled coil assemblies and provides guidance for their design.
Histidine (His, H) undergoes various post-translational modifications (PTMs) and plays multiple roles in protein interactions and enzyme catalyzed reactions. However, comparing with other amino acids such as Lys or Cys,...
Anti-apoptotic B cell lymphoma 2 (BCL-2) family proteins are proven targets for human cancers. Targeting the BH3-binding pockets of these anti-apoptotic proteins could reactivate apoptosis in BCL-2-depedent cancers. BFL-1 is a BCL-2 family protein overexpressed in various chemoresistant cancers. A unique cysteine at the binding interface of the BH3 and BFL-1 was previously proven to be an intriguing targeting site to irreversibly inhibit BFL-1 functions with stabilized cyclic peptide bearing a covalent warhead. Recently, we developed a sulfonium-tethered peptide cyclization strategy to construct peptide ligands that could selectively and efficiently react with the cysteine(s) of target proteins near the interacting interface. Using this method, we constructed a BFL-1 peptide inhibitor, B4-MC, that could selectively conjugate with BFL-1 both in vitro and in cell. B4-MC showed good cellular uptake, colocalized with BFL-1 on mitochondria, and showed obvious growth inhibition of BFL-1 over-expressed cancer cell lines.
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