Mapping the Binding Hotspots and Transient Binding Pockets on V-Domain Immunoglobulin Suppressor of T Cell Activation Protein Surface.

V-domain immunoglobulin suppressor of T cell activation (VISTA), an inhibitory immune checkpoint present on both immune and tumor cells, has emerged as a highly promising target for cancer therapy due to its potential to overcome resistance encountered with existing immune checkpoint treatments. VSIG-3 is determined as an inhibitory ligand for VISTA, leading to the suppression of T cell proliferation. However, hotspots between VISTA/VSIG-3 protein-protein interaction remain ambiguous, mainly attributed to the lack of the structure of the VISTA/VSIG-3 complex.

Virtual Screening and Biological Evaluation of Natural Products as Novel VPS34 Inhibitors that Modulate Autophagy.

VPS34 is a sole member of class III phosphoinositide 3-kinase involved in endosomal trafficking and autophagosome formation, making it an interesting target for cancer treatment. Here, we investigated 5,774 natural products using structure-based virtual screening against human VPS34. 10 natural products identified by virtual screening were purchased and tested in VPS34 ADP-Glo assay, yielding several potential VPS34 inhibitors.

Paneth cell differentiation associated with neoadjuvant therapy in esophageal adenocarcinoma.

Objectives: Paneth cells and Paneth cell metaplasia are well-known in pathology as foundational components in the gastrointestinal system. When within malignant cells (Paneth cell differentiation [PCD]), however, the function and significance of these cells is less well understood. Here, we present findings from the first study focused on PCD in postneoadjuvant esophageal adenocarcinoma (EAC) resection specimens.

Inhibition of bacterial RNA polymerase function and protein-protein interactions: a promising approach for next-generation antibacterial therapeutics.

The increasing prevalence of multidrug-resistant pathogens necessitates the urgent development of new antimicrobial agents with innovative modes of action for the next generation of antimicrobial therapy. Bacterial transcription has been identified and widely studied as a viable target for antimicrobial development. The main focus of these studies has been the discovery of inhibitors that bind directly to the core enzyme of RNA polymerase (RNAP).

Sulfonamidyl derivatives of sigmacidin: Protein-protein interaction inhibitors targeting bacterial RNA polymerase and sigma factor interaction exhibiting antimicrobial activity against antibiotic-resistant bacteria.

RNA polymerase is an essential enzyme involved in bacterial transcription, playing a crucial role in RNA synthesis. However, it requires the association with sigma factors to initiate this process. In our previous work, we utilized a structure-based drug discovery approach to create benzoyl and benzyl benzoic acid compounds.

Ligand-Based Drug Design of Novel Antimicrobials against by Targeting Bacterial Transcription.

is a common human commensal pathogen that causes a wide range of infectious diseases. Due to the generation of antimicrobial resistance, the pathogen becomes resistant to more and more antibiotics, resulting in methicillin-resistant (MRSA) and even multidrug-resistant (MDRSA), namely 'superbugs'. This situation highlights the urgent need for novel antimicrobials.

A ratiometric fluorescence probe for selective and sensitive detection of leucine aminopeptidase in lysosome.

We designed a novel ratiometric fluorescent probe P1-Leu with a donor-acceptor-donor fluorophore for the detection of leucine aminopeptidase in lysosomes. P1-Leu exhibits a lower detection limit than the ratiometric donor-π-acceptor probe, due to the low ratiometric background. Besides, P1-Leu has good lysosome-targeting ability and realizes the distinction of LAP levels in different cells.

QSAR, Docking, and Molecular Dynamics Simulation Studies of Sigmacidins as Antimicrobials against .

are a family of bacterial species significantly affecting human health. In addition, environmental represent one of the major causes of diverse livestock diseases. Due to antimicrobial resistance, there is an urgent need for novel antimicrobial agent discovery against .

Inhibition of Influenza Virus Replication by Oseltamivir Derivatives.

Characterized by the high morbidity and mortality and seasonal surge, the influenza virus (IV) remains a major public health challenge. Oseltamivir is commonly used as a first-line antiviral. As a neuraminidase inhibitor, it attenuates the penetration of viruses through the mucus on the respiratory tract and inhibits the release of virus progeny from infected cells.

Design, Synthesis, Biological Evaluation and In Silico Studies of Pyrazole-Based NH-Acyl Oseltamivir Analogues as Potent Neuraminidase Inhibitors.

Oseltamivir represents one of the most successful neuraminidase (NA) inhibitors in the current anti-influenza therapy. The 150-cavity of NA was identified as an additional binding pocket, and novel NA inhibitors have been designed to occupy the 150-cavity based on the structure information of oseltamivir carboxylate () in complex with NA. In this study, a series of C-5-NH-acyl derivatives of containing the pyrazole moiety were synthesized.

Benzyl and benzoyl benzoic acid inhibitors of bacterial RNA polymerase-sigma factor interaction.

Transcription is an essential biological process in bacteria requiring a core enzyme, RNA polymerase (RNAP). Bacterial RNAP is catalytically active but requires sigma (σ) factors for transcription of natural DNA templates. σ factor binds to RNAP to form a holoenzyme which specifically recognizes a promoter, melts the DNA duplex, and commences RNA synthesis.

Severe recurrent Streptobacillus moniliformis endocarditis in a pregnant woman, and review of the literature.

Background: Rat bite fever is a systemic febrile illness caused by infection with the Gram-negative bacillus Streptobacillus moniliformis following a bite, scratch, or contact with excrement. Only 26 cases of native valve endocarditis have been reported to date. We could find no other reports of severe Streptobacillus endocarditis requiring valve replacement in a young, pregnant patient.

Discovery of Antibacterials That Inhibit Bacterial RNA Polymerase Interactions with Sigma Factors.

Formation of a bacterial RNA polymerase (RNAP) holoenzyme by a catalytic core RNAP and a sigma (σ) initiation factor is essential for bacterial viability. As the primary binding site for the housekeeping σ factors, the RNAP clamp helix domain represents an attractive target for novel antimicrobial agent discovery. Previously, we designed a pharmacophore model based on the essential amino acids of the clamp helix, such as R278, R281, and I291 ( numbering), and identified hit compounds with antimicrobial activity that interfered with the core-σ interactions.

Novel N-Substituted oseltamivir derivatives as potent influenza neuraminidase inhibitors: Design, synthesis, biological evaluation, ADME prediction and molecular docking studies.

The discovery of novel potent neuraminidase (NA) inhibitors remains an attractive approach for treating infectious diseases caused by influenza. In this study, we describe the design and synthesis of novel N-substituted oseltamivir derivatives for probing the 150-cavity which is nascent to the activity site of NA. NA inhibitory studies showed that new derivatives demonstrated the inhibitory activity with IC values at nM level against NA of a clinical influenza virus strain.

First-In-Class Inhibitors Targeting the Interaction between Bacterial RNA Polymerase and Sigma Initiation Factor Affect the Viability and Toxin Release of .

Novel antimicrobial classes are in desperate need for clinical management of infections caused by increasingly prevalent multi-drug resistant pathogens. The protein-protein interaction between bacterial RNA polymerase (RNAP) and the housekeeping sigma initiation factor is essential to transcription and bacterial viability. It also presents a potential target for antimicrobial discovery, for which a hit compound () was previously identified from a pharmacophore model-based screen.

Simple Method for Studying in Vitro Protein-Protein Interactions Based on Protein Complementation and Its Application in Drug Screening Targeting Bacterial Transcription.

Protein-protein interactions (PPIs) underpin essential cellular processes of all organisms and are increasingly considered as drug targets. A number of techniques have been established to study PPIs; however, development of a simple and cost-effective method for in vitro high throughput screening of PPI inhibitors is still in demand or desirable. We report herein a simple method based on protein complementation for the in vitro study of PPIs, as well as screening of inhibitors against the PPI of interest.

Discovery of a potent tyrosine kinase AXL inhibitor bearing the 3-((2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)amino)pyrazine core.

Starting from the recently launched FLT3/AXL multi-targeted inhibitor Gilteritinib (5), we conducted a side-chain ring closure medicinal chemistry approach leading to the identification of compound 15c as a highly potent AXL inhibitor in the biochemical and cellular anti-proliferative assays, with IC values of 1.2 and 0.3 nM, respectively.

Conjugation of Phthalocyanine Photosensitizer with Poly(amidoamine) Dendrimer: Improved Solubility, Disaggregation and Photoactivity Against HepG2 Cells.

Objective: To improve solubility and to reduce aggregation, ZnPcC4 was conjugated to a third-generation poly-amidoamine dendrimer with amino end group (G3-PAMAM-NH2), which acts as a novel photodynamic therapy (PDT) drug carrier system.

Methods: The phthalocyanines were synthesized by construction reaction. The nano drug was obtained from the conjugation of ZnPcC4 to G3-PAMAM-NH2, using EDC and NHS as coupling agents.

Genetic analysis of a morphologically heterogeneous ovarian endometrioid carcinoma.

Aims: Low-grade ovarian endometrioid carcinomas may be associated with high-grade components. Whether the latter are clonally related to and originate from the low-grade endometrioid carcinoma remains unclear. The aim of this study was to use massively parallel sequencing to characterize the genomic landscape and clonal relatedness of an ovarian endometrioid carcinoma containing low-grade and high-grade components.

Anti-inflammatory effect of the six compounds isolated from Nauclea officinalis Pierrc ex Pitard, and molecular mechanism of strictosamide via suppressing the NF-κB and MAPK signaling pathway in LPS-induced RAW 264.7 macrophages.

Ethnopharmacological Relevance: Nauclea officinalis Pierrc ex Pitard. is a Chinese medicinal herb that contains high level of alkaloids which is the most abundant and active constituent. Strictosamide isolated from Nauclea officinalis Pierrc ex Pitard.

Enhanced fluorescence of tetrasulfonated zinc phthalocyanine by graphene quantum dots and its application in molecular sensing/imaging.

When excited at 435 nm, tetra-sulfonate zinc phthalocyanine (ZnPcS ) emitted dual fluorescence at 495 and 702 nm. The abnormal fluorescence at 495 nm was experimentally studied and analyzed in detail for the first time. The abnormal fluorescence at 495 nm was deduced to originate from triplet-triplet (T-T) energy transfer of excited phthalocyanine ( *ZnPcS ).

Design and discovery of 4-anilinoquinazoline-urea derivatives as dual TK inhibitors of EGFR and VEGFR-2.

EGFR and VEGFR-2 are involved in pathological disorders and the progression of different kinds of tumors, the combined blockade of EGFR and VEGFR signaling pathways appears to be an attractive approach to cancer therapy. In this work, a series of 4-anilinoquinazoline derivatives containing substituted diaryl urea or glycine methyl ester moiety were designed and identified as EGFR and VEGFR-2 dual inhibitors. Compounds 19i, 19j and 19l exhibited the most potent inhibitory activities against EGFR (IC = 1 nM, 78 nM and 51 nM, respectively) and VEGFR-2 (IC = 79 nM, 14 nM and 14 nM, respectively), they showed good antiproliferative activities as well.

Nauclea officinalis inhibits inflammation in LPS-mediated RAW 264.7 macrophages by suppressing the NF-κB signaling pathway.

Ethnopharmacological Relevance: Nauclea officinalis has been traditionally used in China for the treatment of fever, pneumonia and enteritidis etc. This study aims to investigate effects of N. officinalis on the inflammatory response as well as the possible molecular mechanism in LPS-stimulated RAW 264.

Structure and multistate function of the transmembrane electron transporter CcdA.

The mechanism by which transmembrane reductases use a single pair of cysteine residues to relay electrons between protein substrates across biological membranes is a long-standing mystery in thiol-redox biochemistry. Here we show the NMR structure of a reduced-state mimic of archaeal CcdA, a protein that transfers electrons across the inner membrane, by using a redox-active NMR sample. The two cysteine positions in CcdA are separated by 20 Å.