piSTING: A Pocket-Independent Agonist Based on Multivalency-Driven STING Oligomerization.

The stimulator of interferon genes (STING) pathway is a potent therapeutic target for innate immunity. Despite the efforts to develop pocket-dependent small-molecule STING agonists that mimic the endogenous STING ligand, cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), most of these agonists showed disappointing results in clinical trials owing to the limitations of the STING pocket. In this study, we developed novel pocket-independent STING-activating agonists (piSTINGs), which act through multivalency-driven oligomerization to activate STING.

Isobaric Stable Isotope N-Phosphorylation Labeling (iSIPL) for Ultrasensitive Proteome Quantification.

Stable isotope chemical labeling methods have been widely used for high-throughput mass spectrometry (MS)-based quantitative proteomics in biological and clinical applications. However, the existing methods are far from meeting the requirements for high sensitivity detection. In the present study, a novel isobaric stable isotope N-phosphorylation labeling (iSIPL) strategy was developed for quantitative proteome analysis.

Dynamic Refolding of OxyS sRNA by the Hfq RNA Chaperone.

The Sm protein Hfq chaperones small non-coding RNAs (sRNAs) in bacteria, facilitating sRNA regulation of target mRNAs. Hfq acts in part by remodeling the sRNA and mRNA structures, yet the basis for this remodeling activity is not understood. To understand how Hfq remodels RNA, we used single-molecule Förster resonance energy transfer (smFRET) to monitor conformational changes in OxyS sRNA upon Hfq binding.

Chinese Medicine Meets Conventional Medicine in Targeting COVID-19 Pathophysiology, Complications and Comorbidities.

Objective: To investigate how the National Health Commission of China (NHCC)-recommended Chinese medicines (CMs) modulate the major maladjustments of coronavirus disease 2019 (COVID-19), particularly the clinically observed complications and comorbidities.

Methods: By focusing on the potent targets in common with the conventional medicines, we investigated the mechanisms of 11 NHCC-recommended CMs in the modulation of the major COVID-19 pathophysiology (hyperinflammations, viral replication), complications (pain, headache) and comorbidities (hypertension, obesity, diabetes). The constituent herbs of these CMs and their chemical ingredients were from the Traditional Chinese Medicine Information Database.

STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation.

Unlabelled: Immunostimulatory therapies based on pattern recognition receptors (PRRs) have emerged as an effective approach in the fight against cancer, with the ability to recruit tumor-specific lymphocytes in a low-immunogenicity tumor environment. The agonist cyclic dinucleotides (CDNs) of the stimulator of interferon gene (STING) are a group of very promising anticancer molecules that increase tumor immunogenicity by activating innate immunity. However, the tumor immune efficacy of CDNs is limited by several factors, including relatively narrow cytokine production, inefficient delivery to STING, and rapid clearance.

A chitosan-mediated inhalable nanovaccine against SARS-CoV-2.

Unlabelled: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with several antigenic variants, has grown into a global challenge, and the rapid establishment of an immune barrier is crucial to achieving long-term control of the virus. This has led to a great demand for easy preparation and scalable vaccines, especially in low-income countries. Here, we present an inhalable nanovaccine comprising chitosan and SARS-CoV-2 spike protein.

Synthesis of Dipeptide, Amide, and Ester without Racemization by Oxalyl Chloride and Catalytic Triphenylphosphine Oxide.

An efficient triphenylphosphine oxide-catalyzed amidation and esterification for the rapid synthesis of a series of dipeptides, amides, and esters is described. This reaction is applicable to challenging couplings of hindered carboxylic acids with weakly nucleophilic amines or alcohols, giving the products in good yields (67-90%) without racemization. This system employs the highly reactive intermediate PhPCl as the activator of the carboxylate in a catalytic manner and drives the reaction to completion in a short reaction time (less than 10 min).

Different phosphorylation and farnesylation patterns tune Rnd3-14-3-3 interaction in distinct mechanisms.

Protein posttranslational modifications (PTMs) are often involved in the mediation or inhibition of protein-protein interactions (PPIs) within many cellular signaling pathways. Uncovering the molecular mechanism of PTM-induced multivalent PPIs is vital to understand the regulatory factors to promote inhibitor development. Herein, Rnd3 peptides with different PTM patterns as the binding epitopes and 14-3-3ζ protein were used as models to elucidate the influences of phosphorylation and farnesylation on binding thermodynamics and kinetics and their molecular mechanism.

Recent Advances in Small Peptides of Marine Origin in Cancer Therapy.

Cancer is one of the leading causes of death in the world, and antineoplastic drug research continues to be a major field in medicine development. The marine milieu has thousands of biological species that are a valuable source of novel functional proteins and peptides, which have been used in the treatment of many diseases, including cancer. In contrast with proteins and polypeptides, small peptides (with a molecular weight of less than 1000 Da) have overwhelming advantages, such as preferential and fast absorption, which can decrease the burden on human gastrointestinal function.

Engineering of stepwise-targeting chitosan oligosaccharide conjugate for the treatment of acute kidney injury.

Acute kidney injury (AKI) is a common and serious clinical syndrome of acute renal dysfunction in a short period. One of therapeutic interventions for AKI is to reduce ROS massively generated in the mitochondria and then ameliorate cell damage and apoptosis induced by oxidative stress. In this study, stepwise-targeting chitosan oligosaccharide, triphenyl phosphine-low molecular weight chitosan-curcumin (TPP-LMWC-CUR, TLC), was constructed for sepsis-induced AKI via removing excessive ROS in renal tubular epithelial cells.

Visible-Light-Induced Phosphorylation of Imidazo-Fused Heterocycles under Metal-Free Conditions.

A metal-free and base-free procedure for the phosphorylation of imidazo[1,2-]pyridines with phosphine oxides under the irradiation of visible light at room temperature in green solvent was reported, featuring mild and sustainable conditions, convenient operation, as well as good functional group compatibility.

Fully Synthetic Invariant NKT Cell-Dependent Self-Adjuvanting Antitumor Vaccines Eliciting Potent Immune Response in Mice.

Constructing an effective therapeutic cancer vaccine is very attractive and promising for cancer immunotherapy. However, the poor immunogenicity of tumor antigens and suppression of the immune system in the tumor microenvironment are two major obstacles for developing effective cancer vaccines. Invariant NKT cells (iNKT cells), which are essential bridges between the innate and adaptive immune systems, can be rapidly activated by their agonists and, consequently, evoke whole immune systems.

Inhibition of K-Ras4B-plasma membrane association with a membrane microdomain-targeting peptide.

The association of K-Ras4B protein with plasma membrane (PM) is required for its signaling activity. Thus, direct inhibition of K-Ras4B-PM interaction could be a potential anti-Ras therapeutic strategy. However, it remains challenging to modulate such protein-PM interaction.

Visible-Light Induced Radical Perfluoroalkylation/Cyclization Strategy To Access 2-Perfluoroalkylbenzothiazoles/Benzoselenazoles by EDA Complex.

A novel and practical fluoroalkyl radical-initiated cascade reaction was developed to access diverse 2-fluoroalkylbenzothiazoles by reacting various fluoroalkyl radical sources, including perfluoroalkyl iodide (IC F, n = 3-8, 10), ICF(CF), ICFCOOEt, ICFCFCl, or ICFCFBr, tetramethylethane-1,2-diamine (TMEDA), and 2-isocyanoaryl thioethers in tetrahydrofuran under nitrogen atmosphere and blue-light irradiation conditions. Furthermore, this one-pot protocol could well be expanded to access various 2-fluoroalkylbenzoselenazoles starting from (2-isocyanophenyl)(methyl)selane, perfluoroalkyl iodides (IC F, n = 3-8) or ICFCOOEt and TMEDA.

Plasminogen activator, tissue type regulates germinal vesicle breakdown and cumulus expansion of bovine cumulus-oocyte complex in vitro†.

Plasminogen activator, tissue type (PLAT) and its inhibitor serpin family E member 1 (SERPINE1) cooperatively regulate PLAT activity in various reproductive processes. However, it is unknown whether this includes bovine oocyte maturation. We addressed this question in the present study by evaluating PLAT and SERPINE1 protein localization in immature cumulus-oocyte complexes (COCs), as well as PLAT mRNA and protein expression in cultured COCs after 0, 8, 16, and 24 h of in vitro maturation (IVM).

Silver-catalyzed decarboxylative radical cascade cyclization toward benzimidazo[2,1-a]isoquinolin-6(5H)-ones.

A simple and efficient decarboxylative radical addition/cyclization strategy was developed, by which a wide range of benzimidazo[2,1-a]isoquinoline-6(5H)-ones were prepared in one-pot via reaction of functionalized 2-arylbenzoimidazoles and carboxylic acids in the presence of K2S2O8/AgNO3 under mild reaction conditions.

Exploring the Roles of Post-Translational Modifications in the Pathogenesis of Parkinson's Disease Using Synthetic and Semisynthetic Modified α-Synuclein.

Alpha-synuclein (α-syn), a small soluble protein containing 140 amino acids, is associated with the recycling pool of synaptic vesicles in presynaptic terminals. The misfolding and aggregation of α-syn is closely related to a group of neurodegenerative diseases, including Parkinson's disease (PD), which is one of the most common progressive neurodegenerative diseases. Varieties of the post-translational modifications (PTMs) of α-syn, including phosphorylation, ubiquitination, and glycosylation, have been detected in soluble and aggregated α-syn in vivo.

TDP-43 specific reduction induced by Di-hydrophobic tags conjugated peptides.

TAR DNA binding protein 43 (TDP-43) is a key target in amyotrophic lateral sclerosis (ALS) treatment. Here, based on hydrophobic tagging strategy, we designed and synthesized a series of single or double hydrophobic tags conjugated peptides D1-D8. Among them, it was found that D4 displayed strongest ability to induce TDP-43 degradation in cells.

Copper-Catalyzed Radical Cascade Cyclization To Access 3-Sulfonated Indenones with the AIE Phenomenon.

An efficient copper-catalyzed radical cascade cyclization strategy was developed, by which a wide variety of 3-sulfonyl substituted indenones were prepared in one pot via reaction of 2-alkynylbenzonitriles with sulfonyl hydrazides in the presence of TBHP and CuI under mild reaction conditions. Much more importantly, the 3-sulfonyl indenones, synthesized through our newly developed copper-catalyzed radical cascade cyclization strategy, were found to own typical aggregation-induced emission (AIE) properties, showing orange to red emission with large Stokes shift (more than 135 nm). In addition, such newly found AIEgens could be successfully used in live cell imaging, exhibiting excellent biocompatibility and application potential.

Phosphorus Radical-Initiated Cascade Reaction To Access 2-Phosphoryl-Substituted Quinoxalines.

An effective radical cascade cyclization strategy was developed, by which a wide range of 2-phosphoryl-substituted quinoxalines were prepared in one pot via reaction of ortho-diisocyanoarenes with diarylphosphine oxides in the presence of AgNO under mild reaction conditions.

Targeting STING with cyclic di-GMP greatly augmented immune responses of glycopeptide cancer vaccines.

Cyclic di-GMP (CDG) was applied to MUC1 glycopeptide-based cancer vaccines with physical mixing and built-in (at 2'-OH of CDG) strategies for activating the STING pathway. CDG in both strategies behaved as a potent immunostimulant and contributed to high titers of IgG antibodies and the expression of multiple cytokines.

Differential Modulation of the Aggregation of N-Terminal Truncated Aβ using Cucurbiturils.

Modulating the aggregation of Aβ has long been considered to be one of the potential methods to treat Alzheimer's disease (AD). It has been found that different Aβ species, including N-terminal truncated or/and modified Aβ, co-exist in the brain of AD patients. Yet, there is currently little detailed work about the specific modulation of these Aβ species which hinders us to understand their roles in patients' brain.

De Novo Design To Synthesize Lanthipeptides Involving Cascade Cysteine Reactions: SapB Synthesis as an Example.

Lanthipeptides are a family of ribosomally synthesized peptides that have crucial biological functions. However, due to their complicated structures, the total synthesis of lanthipeptides is challenging. Here, a novel strategy to construct lanthipeptides is described, which involves cascade reactions of cysteine, including Cys disalkylation elimination, Michael reaction, and native chemical ligation.

Selective inhibition of cancer cells by enzyme-induced gain of function of phosphorylated melittin analogues.

The selective killing of cancer cells and the avoidance of drug resistance are still difficult challenges in cancer therapy. Here, we report a new strategy that uses enzyme-induced gain of function (EIGF) to regulate the structure and function of phosphorylated melittin analogues (MelAs). Original MelAs have the capacity to disrupt plasma membranes and induce cell death without selectivity.