A5064998778- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- CRISPR and Genetic Engineering
- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Glycosylation and Glycoproteins Research
- RNA and protein synthesis mechanisms
- Protein Tyrosine Phosphatases
- Multiple Myeloma Research and Treatments
- 14-3-3 protein interactions
- Protein Degradation and Inhibitors
- Bacterial Genetics and Biotechnology
- Immune Cell Function and Interaction
- Computational Drug Discovery Methods
- Advanced biosensing and bioanalysis techniques
- Cancer therapeutics and mechanisms
- SARS-CoV-2 and COVID-19 Research
- Bacteriophages and microbial interactions
- Immunotherapy and Immune Responses
- Lung Cancer Treatments and Mutations
- Synthesis and Biological Evaluation
- Plant Virus Research Studies
- RNA regulation and disease
- Plant biochemistry and biosynthesis
- Antibiotic Resistance in Bacteria
China Pharmaceutical University
2018-2025
State Key Laboratory of Natural Medicine
2021-2024
Ministry of Education of the People's Republic of China
2024
Cornell University
2017
University of Lübeck
2011-2012
Wuhan University
2008
Several monoclonal antibodies targeting the programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway have been used successfully in anticancer immunotherapy. Inherent limitations of antibody-based therapies remain, however, and alternative small-molecule inhibitors that can block PD-1/PD-L1 axis are urgent needed. Herein, we report discovery compound 17 as a bifunctional inhibitor interactions. inhibits interactions promotes dimerization, internalization, degradation PD-L1....
VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint protein and represents promising target for cancer immunotherapy. Here, we report the design, synthesis, evaluation series methoxy-pyrimidine-based small molecule inhibitors with potent antitumor activity. By employing molecular docking microscale thermophoresis (MST) assay, identified lead compound A1 that binds to high affinity optimized its structure. A4 was then obtained, which exhibited strongest binding...
Abstract Type I CRISPR-Cas systems employ multi-subunit effector Cascade and helicase-nuclease Cas3 to target degrade foreign nucleic acids, representing the most abundant RNA-guided adaptive immune in prokaryotes. Their ability cause long fragment deletions have led increasing interests eukaryotic genome editing. While structures of all other six type been determined, structure evolutionarily conserved I-B is still missing. Here, we present two cryo-EM Synechocystis sp . PCC 6714 ( Syn )...
ABSTRACT Nonstructural proteins 7 and 8 of severe acute respiratory syndrome coronavirus (SARS-CoV) have previously been shown by X-ray crystallography to form an 8:8 hexadecamer. In addition, it has demonstrated that N-terminally His 6 -tagged SARS-CoV Nsp8 is a primase able synthesize RNA oligonucleotides with length up nucleotides. We present here the 2.6-Å crystal structure feline (FCoV) Nsp7:Nsp8 complex, which 2:1 heterotrimer containing two copies α-helical Nsp7 conformational...
Despite considerable therapeutic advances, there is still a dearth of evidence on the molecular determinants cardiac hypertrophy that culminate in heart failure. Neuraminidases are family enzymes catalyze cleavage terminal sialic acids from glycoproteins or glycolipids. This study sought to characterize role neuraminidases pathological and identify pharmacological inhibitors targeting mammalian neuraminidases.Neuraminidase 1 (NEU1) was highly expressed hypertrophic hearts mice rats, this...
Osimertinib resistance is an unmet clinical need for the treatment of non-small cell lung cancer (NSCLC), and main mechanism tertiary C797S mutation epidermal growth factor receptor (EGFR). To date, there no inhibitor approved Osimertinib-resistant NSCLC. Herein, we reported a series derivatives as fourth-generation inhibitors which were rationally designed. Top candidate D51 potently inhibited EGFRL858R/T790M/C797S mutant with IC50 value 14 nM suppressed proliferation H1975-TM cells nM,...
EGFRT790M mutation causes resistance to the first-generation tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, therapeutic options for sensitizing first TKIs and delaying emergence of mutant are limited. In this study, we show that quercetin directly binds glucose-6-phosphate dehydrogenase (G6PD) inhibits its enzymatic activity through competitively abrogating NADP+ binding catalytic domain. This inhibition subsequently reduces intracellular...
The epidermal growth factor receptor (EGFR) tertiary C797S mutation is an important cause of resistance to Osimertinib, which seriously hinders the clinical application Osimertinib. Developing proteolysis-targeting chimeras (PROTACs) targeting EGFR mutants can offer a promising strategy overcome drug resistance. In this study, some novel PROTACs were designed and synthesized based on new inhibitor displayed potent degradation effect in H1975-TM cells harboring EGFRL858R/T790M/C797S....
Blocking the PD-1/PD-L1 interaction has become an important strategy for tumor therapy, which shown outstanding therapeutic effects in clinical settings. However, unsatisfactory response rates and immune-related adverse limit use of anti-PD1/PD-L1 antibodies. Here, we report discovery identification S4-1, innovative small-molecule inhibitor PD-L1. In vitro, S4-1 effectively altered PD-L1/PD-1 interaction, induced PD-L1 dimerization internalization, improved its localization to endoplasmic...
The two proteases, PLpro and Mpro, of SARS-CoV-2 are essential for replication the virus. Using a structure-based co-pharmacophore screening approach, we developed novel dual-targeted inhibitor that is equally potent in inhibiting Mpro SARS-CoV-2. contains warhead, which can form covalent bond with catalytic cysteine residue either enzyme. maximum rate inactivation comparable to most inhibitors reported viral proteases drugs currently clinical use. inhibition appears be very specific...
Currently, multiple myeloma (MM) is still an incurable plasma cell malignancy in urgent need of novel therapeutic targets and drugs.Bufalin was known as a highly toxic but effective anti-cancer compound. We used Bufalin probe to screen its potential by proteome microarray, which AHSA1 the unique target Bufalin. The effects on cellular proliferation drug resistance were determined MTT, western blot, flow cytometry, immunohistochemistry staining xenograft model vivo. mechanisms KU-177...
Programmed cell death 1(PD-1)/programmed ligand 1(PD-L1) have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy. Despite inherent advantages small-molecule inhibitors over antibodies, discovery has fallen behind that antibody drugs. Based on docking studies between small molecule inhibitor and PD-L1 protein, changing chemical linker from a flexible chain to an aromatic ring may improve its binding capacity which was not reported before. A series novel...
Current small-molecule PD-1/PD-L1 inhibitors are mainly based on the arylmethylamine/biphenyl core scaffold. Herein, we designed for first time a series of non-arylmethylamine analogues (oxadiazole thioether derivatives) as inhibitors. Among them, compound LP23 exhibited most potent PD-L1 inhibitory activity with an IC50 16.7 nM, 3.2-fold better than lead BMS-202 (IC50 = 53.6 nM). The X-ray crystal structure in complex was solved at resolution 2.6 Å, which further confirmed high binding...
Pyran- and furanocoumarins are key representatives of tetrahydropyrans tetrahydrofurans, respectively, exhibiting diverse physiological medical bioactivities. However, the biosynthetic mechanisms for their core remain poorly understood. Here we combined multiomics analyses enzymes in Peucedanum praeruptorum vitro functional verification identified two types critical pyran furan ring biosynthesis plants. These included three distinct P. prenyltransferases (PpPT1–3) responsible prenylation...
Immune checkpoint inhibitors (ICIs) have been potent therapeutic options for the treatment of multiple types cancer. However, not all patients experience benefits from ICIs, and discovering targeting novel immune checkpoints is necessary. V-domain Ig suppressor T-cell activation (VISTA) a checkpoint. Blockade VISTA pathway enhances antitumor immunity in tumor types. Herein, series based on benzimidazole scaffold were discovered. B3 showed strongest binding affinity to protein with KD value...
<title>Abstract</title> Cyclic oligonucleotide-based antiphage signaling systems (CBASS) are widespread bacterial immune that trigger host suicide via cyclic nucleotide-activated effectors. The predominant strategy to induce cell death in CBASS is membrane disruption. Here, we demonstrate patatin-like phospholipase CapV, the most abundant effector, relocates and cleaves phospholipids at pole upon 3’3’-cGAMP binding, inducing polarized disruption death. Using cryo-EM, reveal apo-CapV adopts...
Several antibodies targeting programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) have been approved by the U.S. Food and Drug Administration (FDA) for cancer therapy. Although many small-molecule inhibitors of PD-1/PD-L1 pathway reported, no treatment. In this work, a series novel benzamide derivatives were designed, synthesized, evaluated to find effective interaction. The most potent compound D2 exhibited better activity than that BMS202, with an IC50 16.17 nM. could activate...
Tumor cells can evade immune surveillance through overexpressing programmed cell death-ligand 1 (PD-L1) to interact with death-1 (PD-1). Besides, tumor-intrinsic PD-L1 is involved in tumor progression without interaction PD-1, which provides more challenges for the discovery of inhibitors. Herein, we report novel inhibitors using fragment coupling strategy. Among them, B9 was found inhibit PD-1/PD-L1 best IC50 value 1.8 ± 0.7 nM. Beyond blockade axis, promotes dimerization, internalization,...
Prostate cancer (PCa) is a common male with high incidence and mortality, hormonal therapy as the major treatment for PCa patients troubled by inevitable resistance that makes us identify novel targets PCa. Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) was found to be an effective target of PCa, but research on its inhibitors rather little. In this work, potent DYRK2 inhibitor 43 (IC50 = 0.6 nM) acquired through virtual screening structural optimization, which...