Development of cyclopeptide inhibitors of cGAS targeting protein-DNA interaction and phase separation.

Cyclic GMP-AMP synthase (cGAS) is an essential sensor of aberrant cytosolic DNA for initiating innate immunity upon invading pathogens and cellular stress, which is considered as a potential drug target for autoimmune and autoinflammatory diseases. Here, we report the discovery of a class of cyclopeptide inhibitors of cGAS identified by an in vitro screening assay from a focused library of cyclic peptides. These cyclopeptides specifically bind to the DNA binding site of cGAS and block the binding of dsDNA with cGAS, subsequently inhibit dsDNA-induced liquid phase condensation and activation of cGAS.

Caged Luciferase Inhibitor-Based Bioluminescence Switching Strategy Enables Efficient Detection of Serum APN Activity and the Identification of Its Roles in Metastasis of Non-Small Cell Lung Cancer.

Bioluminogenic probes emerged as powerful tools for imaging and analysis of various bioanalyses, but traditional approaches would be limited to the low sensitivity during determine the low activity of protease in clinical specimens. Herein, we proposed a caged luciferase inhibitor-based bioluminescence-switching strategy (CLIBS) by using a cleavable luciferase inhibitor to modulate the activity of luciferase reporter to amplify the detective signals, which led to the enhancement of detection sensitivity, and enabled the determination of circulating Aminopeptidase N (APN) activity in thousands of times diluted serum. By applying the CLIBS to serum samples in non-small cell lung cancer (NSCLC) patients from two clinical cohorts, we revealed that, for the first time, higher circulating APN activities but not its concentration, were associated with more NSCLC metastasis or higher metastasis stages by subsequent clinical analysis, and can serve as an independent factor for forecasting NSCLC patients' risk of metastasis.

Blockade of USP14 potentiates type I interferon signaling and radiation-induced antitumor immunity via preventing IRF3 deubiquitination.

Purpose: The adaptive immune responses induced by radiotherapy has been demonstrated to largely rely on STING-dependent type I interferons (IFNs) production. However, irradiated tumor cells often fail to induce dendritic cells (DCs) to produce type I IFNs. Hence, we aim to uncover the limitation of STING-mediated innate immune sensing following radiation, and identify efficient reagents capable to rescue the failure of type I IFNs induction for facilitating radiotherapy.

Identification of 2-Benzylidene-tetralone Derivatives as Highly Potent and Reversible Firefly Luciferase Inhibitors.

The extensive applications of Firefly luciferase (Fluc) in numerous biological, biomedical, and clinical investigations rendered an urgent need for efficient and biocompatible Fluc inhibitors for the construction of novel assay platforms. Herein we describe the identification of 2-benzylidene-tetralone derivatives as highly potent and reversible Firefly luciferase inhibitors by competing with d-luciferin. The most active compound was found to have >7000 fold higher potency (IC = 0.

Degradation of intracellular TGF-β1 by PROTACs efficiently reverses M2 macrophage induced malignant pathological events.

The first proteolysis targeting chimeras for the intracellular elimination of transforming growth factor-β1 (TGF-β1), which contributes to various diseases, are described. The appropriately designed DT-6 could efficiently degrade intracellular TGF-β1, and inhibit M2 macrophage induced epithelial to mesenchymal transition and invasive migration of cancer cells.

Raloxifene alleviates amyloid-β-induced cytotoxicity in HT22 neuronal cells via inhibiting oligomeric and fibrillar species formation.

Raloxifene, a selective estrogen receptor modulator, displays benefits for Alzheimer's disease (AD) prevention in postmenopausal women as hormonal changes during menopause have the potential to influence AD pathogenesis, but the underlying mechanism of its neuroprotection is not entirely clear. In this study, the effects of raloxifene on amyloid-β (Aβ) amyloidogenesis were evaluated. The results demonstrated that raloxifene inhibits Aβ aggregation and destabilizes preformed Aβ fibrils through directly interacting with the N-terminus and middle domains of Aβ peptides.

Dissociation of haemolytic and oligomer-preventing activities of gramicidin S derivatives targeting the amyloid-β N-terminus.

The intrinsic haemolysis of an amyloid-β (Aβ) N-terminal targeting gramicidin S derivative was successfully dissociated from its Aβ oligomer-preventing activities via Ala-scanning-based regulation of molecular amphiphilicity. The representative analogue DGR-7 shows low toxicity but significant efficiency in preventing Aβ oligomers and reducing amyloid plaques in APP/PS1 transgenic AD mice.

Synthesis and evaluation of anticancer activity of BOC26P, an ortho-aryl chalcone sodium phosphate as water-soluble prodrugs in vitro and in vivo.

Major limitations of chalcones as clinical anticancer agents are water insolubility and poor bioavailability, which may be improved by a classic phosphate prodrug strategy that targets non-specific alkaline phosphatase (ALP) for releasing the parent drug in vivo. In this study, we found that BOC26P, a phosphate prodrug of chalcone OC26, exhibits excellent water solubility and improved plasma concentration in vivo by either i.v.

Stabilizing amyloid-β peptide by the N-terminus capture is capable of preventing and eliminating amyloid-β oligomers.

Elimination of amyloid-β (Aβ) oligomers remains challenging. We describe here a novel strategy to prevent and eliminate the Aβ oligomers from either the early aggregation or the fibril dissolution pathway by targeting the flexible N-terminus, but not the widely investigated hydrophobic segment, with a rationally designed cyclopeptide.

Identification of 4-arylidene curcumin analogues as novel proteasome inhibitors for potential anticancer agents targeting 19S regulatory particle associated deubiquitinase.

The proteasomal 19S regulatory particle (RP) associated deubiquitinases (DUBs) have attracted much attention owing to their potential as a therapeutic target for cancer therapy. Identification of new entities against 19S RP associated DUBs and illustration of the underlying mechanisms is crucial for discovery of novel proteasome blockers. In this study, a series of 4-arylidene curcumin analogues were identified as potent proteasome inhibitor by preferentially blocking deubiquitinase function of proteasomal 19S RP with moderate 20S CP inhibition.

Stabilizing the monomeric amyloid-β peptide by tyrocidine A prevents and reverses amyloidogenesis without the accumulation of oligomers.

Amyloid-β (Aβ) oligomers are causative agents triggering AD pathogenesis, but their elimination remains challenging. We herein reported a natural cyclopeptide tyrocidine A prevents and reverses amyloidogenesis without Aβ oligomer accumulation by stabilizing the monomeric, but not the oligomeric state of Aβ peptides.