A5082725852- Traditional and Medicinal Uses of Annonaceae
- Synthetic Organic Chemistry Methods
- Cocoa and Sweet Potato Agronomy
- T-cell and B-cell Immunology
- Chemical Synthesis and Analysis
- Immune Cell Function and Interaction
- Marine Sponges and Natural Products
- Carbohydrate Chemistry and Synthesis
- Microbial Natural Products and Biosynthesis
- Hepatitis C virus research
- Hepatitis B Virus Studies
- Click Chemistry and Applications
- Insect Pest Control Strategies
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Plant and Fungal Species Descriptions
- Photodynamic Therapy Research Studies
- Nanoplatforms for cancer theranostics
- Synthesis and Catalytic Reactions
- Phytochemical compounds biological activities
- Insect-Plant Interactions and Control
- Porphyrin and Phthalocyanine Chemistry
- Marine Toxins and Detection Methods
- Ubiquitin and proteasome pathways
- Immunotherapy and Immune Responses
Children's Hospital of Philadelphia
2018-2024
Roche (China)
2015-2023
Zhejiang Hisun Pharmaceutical (China)
2020-2021
Shanghai Xuhui Central Hospital
2017
The University of Texas Southwestern Medical Center
2015
Fox Chase Cancer Center
2015
Southwestern Medical Center
2015
Roche (Switzerland)
2014
Institute of Medicinal Plant Development
2014
Oklahoma Medical Research Foundation
2010-2013
The YAP-TEAD protein-protein interaction (PPI) mediates the oncogenic function of YAP, and inhibitors this PPI have potential usage in treatment YAP-involved cancers. Here we report design synthesis potent cyclic peptide interaction. A truncation study YAP interface 3 identified YAP(84-100) as a weak inhibitor (IC50 = 37 μM), an alanine scan revealed beneficial mutation, D94A. Subsequent replacement native cation-π with optimized disulfide bridge for conformational constraint synergistic...
Abstract Heteroaryldihydropyrimidine (HAP) and sulfamoylbenzamide (SBA) are promising non-nucleos(t)ide HBV replication inhibitors. HAPs known to promote core protein mis-assembly, but the molecular mechanism of abnormal assembly is still elusive. Likewise, status induced by SBA remains unknown. Here we show that SBA, unlike HAP, does not mis-assembly. Interestingly, two reference compounds HAP_R01 SBA_R01 bind same pocket at dimer-dimer interface in crystal structures Y132A hexamer. The...
Hippo signaling pathway is emerging as a novel target for anticancer therapy because it plays key roles in organ size control and tumorigenesis. As the downstream effectors, Yes-associated protein (YAP)-transcriptional enhancer activation domain family member (TEAD) association essential YAP-driven oncogenic activity, while TEAD largely dispensable normal tissue growth. We present design of YAP-like peptides (17mer) to occupy interface 3 on TEAD. Introducing cysteines at YAP sites 87 96 can...
Platelet-derived growth factor (PDGF) is a mitogen and chemoattractant for vascular smooth muscle cells (VSMCs). However, the direct effects of PDGF receptor β (PDGFRβ) activation on VSMCs have not been studied in context atherosclerosis. Here we present new mouse model atherosclerosis with an activating mutation PDGFRβ. Increased PDGFRβ signalling induces chemokine secretion leads to leukocyte accumulation adventitia media aorta. Furthermore, PDGFRβD849V amplifies accelerates...
The transcriptional enhanced associate domain (TEAD) family of transcription factors serves as the receptors for downstream effectors Hippo pathway, YAP and TAZ, to upregulate expression multiple genes involved in cellular proliferation survival. Recent work identified TEAD S-palmitoylation critical protein stability activity lipid tail extends into a hydrophobic core protein. Here, we report identification characterization potent small molecule that binds pocket (LP) disrupts...
Cytoskeletal alterations in endothelial cells have been linked to nitric oxide generation and cell-cell interactions. Transforming growth factor (TGF)-beta has described affect cytoskeletal rearrangement numerous cell types; however, the underlying pathway is unclear. In present study, we found that human umbilical vein (HUVEC) marked with short-term TGF-beta treatment resulting filipodia formation F-actin assembly. The were blocked by novel type I receptor/ALK5 kinase inhibitor (SB-505124)...
The fundamental role played by actin in the regulation of eukaryotic cell maintenance and motility renders it a primary target for small-molecule intervention. In this arena, class potent cytotoxic cyclodepsipeptide natural products has emerged over last quarter-century to stimulate fields biology chemistry with their unique actin-stabilizing properties complex peptide−polyketide hybrid structures. Despite considerable research effort, structural basis activity these secondary metabolites...
Described herein is the first-time disclosure of Linvencorvir (RG7907), a clinical compound and hepatitis B virus (HBV) core protein allosteric modulator, for treatment chronic HBV infection. Built upon structure hetero aryl dihydropyrimidine, RG7907 was rationally designed by combining all drug-like features low CYP3A4 induction, potent anti-HBV activity, high metabolic stability, hERG liability, favorable animal pharmacokinetic (PK) profiles. In particular, chemistry strategy to mitigate...
Described herein are the discovery and structure–activity relationship (SAR) studies of third-generation 4-H heteroaryldihydropyrimidines (4-H HAPs) featuring introduction a C6 carboxyl group as novel HBV capsid inhibitors. This new series HAPs showed improved anti-HBV activity better drug-like properties compared to first- second-generation HAPs. X-ray crystallographic study analogue 12 (HAP_R01) with Cp149 Y132A mutant hexamer clearly elucidated role played for increased binding affinity,...
A palladium-catalyzed difluoromethylation of a series aryl chlorides and triflates under mild conditions was described. variety common functional groups were tolerated. In addition, by using this protocol, several drug molecules containing an chloride unit successfully difluoromethylated, thus enabling medicinal chemists to rapidly access novel derivatives with potentially improved properties via late-stage functionalization.
iNKT cells derive from CD4+CD8+ DP thymocytes, and are selected by thymocyte-thymocyte interactions through signals their invariant Vα14-Jα18 TCR the costimulatory molecules SLAMF1 SLAMF6. Genetic studies have demonstrated contribution of different signaling pathways to this process. Surprisingly, current models imply that Ras/MAPK pathway, one critical mediators conventional αβ T cell positive selection, is not necessary for development. Using mice defective at levels pathway our results...
The study of classical ring-closing metathesis and relay in a total synthesis Jasplakinolide its desbromo analog is described.
The total synthesis of two mono-THF acetogenins, tonkinecin (1) and annonacin (2), is reported in full detail. Terminal acetylene 3 prepared from d-glucono-δ-lactone asymmetric dihydroxylation was employed as a common intermediate for both targets 1 2. Pd(0)-catalyzed coupling reaction with vinyl iodides 4 5, the chiral centers which were taken d-xylose S-(−)-ethyl lactate, afforded enyne 26 27, respectively. Selective hydrogenation or 27 diimide followed by removal MOM ethers completed 1. A...
Altered calcium [Ca 2+ ] transients of vascular smooth muscle cells to vasoconstrictors may contribute altered regulation blood flow in diabetes. We postulated that diabetes-induced transforming growth factor (TGF)-β production contributes impaired ANG II response macrovessels and microvessels. Aortic isolated from diabetic rats exhibited markedly II-induced cytosolic signal was completely restored by pretreatment with anti-TGF-β antibodies. Similar findings were noted microvascular...
The synthesis of a focused library jasplakinolide analogs with 1,2,3-triazole in place an E-configured double bond is described, featuring the Cu(I) catalyzed azide–alkyne cycloaddition reaction as efficient macrocyclization tool.
Abstract Small, organic, fluorescent molecules with large Stokes shifts and long emission wavelengths are ideal dyes for various modern imaging technologies such as FRET. In this study, we designed synthesized a number of new on the basic structures two pyrrolocoumarin skeletons where Fischer's indole synthesis Suzuki coupling successfully served efficient molecular editing protocols. The examination properties further structural optimization these compounds afforded three notably...
The Fas-associated death domain-containing protein (FADD) is an adaptor for relaying apoptotic signals initiated by receptors such as Fas. Whereas a lack of has no effect on mouse development, FADD deficiency results in early embryonic lethality, indicating that additional functions independent receptors. We have previously shown conditional deletion not only impairs apoptosis but also leads to defective lymphocyte proliferation. non-apoptotic signaling mediated remains poorly understood....
GATA-3 is necessary for the development of MHC class II-restricted CD4 T cells, and its expression increased during positive selection these cells. TCR signals drive this upregulation, but signaling pathways that control process are not well understood. Using genetic pharmacological approaches, we show upregulation thymocyte-positive result additive inputs from Ras/MAPK calcineurin pathways. This requires presence transcription factor c-Myb. Furthermore, TH-POK can also upregulate in...
E protein transcription factors and their natural inhibitors, Id proteins, play critical complex roles during lymphoid development. In this article, we report that partial maintenance of activity positive selection results in a change the cell fate determination developing iNKT cells, with block development iNKT1 cells parallel increase iNKT2 iNKT17 subsets. Because expression levels drive these alternative functional fates (GATA-3, RORγT, T-bet, Runx-3) are not altered, our suggest controls...