A5003205885- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Cancer Immunotherapy and Biomarkers
- Chemical synthesis and alkaloids
- Cellular transport and secretion
- Biomedical and Chemical Research
- Alkaloids: synthesis and pharmacology
- Neuropeptides and Animal Physiology
- Receptor Mechanisms and Signaling
- CAR-T cell therapy research
- Enzyme Catalysis and Immobilization
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Immunodeficiency and Autoimmune Disorders
- Crystallography and molecular interactions
- Synthesis and Characterization of Pyrroles
- Traditional and Medicinal Uses of Annonaceae
- Glycosylation and Glycoproteins Research
- Pharmacological Receptor Mechanisms and Effects
- Cellular Mechanics and Interactions
- Phytochemistry and Bioactivity Studies
- Oxidative Organic Chemistry Reactions
- Bioactive Compounds and Antitumor Agents
- Biochemical and Structural Characterization
- Flexible and Reconfigurable Manufacturing Systems
University College London
2018-2024
Birkbeck, University of London
2024
Institute of Structural and Molecular Biology
2018-2024
Roland Hill (United Kingdom)
2024
Institute of Infection and Immunity
2024
The Royal Free Hospital
2022
Grünenthal Group (Germany)
2014
Institute of Medicinal Plant Development
2014
Ludwig-Maximilians-Universität München
2004-2007
Springer Nature (Germany)
1987
CD28 and CTLA-4 (CD152) play essential roles in regulating T cell immunity, balancing the activation inhibition of responses, respectively. Although both receptors share same ligands, CD80 CD86, specific requirement for two distinct ligands remains obscure. In present study, we demonstrate that, although targets CD86 destruction via transendocytosis, this process results separate fates itself. presence CD80, remained ligand bound, was ubiquitylated trafficked late endosomes lysosomes....
In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed their favorable in vitro vivo pharmacological properties revealed. We herein report further optimize lead 2a, toward trans-6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3′H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently clinical development for treatment...
CD80 and CD86 are expressed on antigen presenting cells required to engage their shared receptor, CD28, for the costimulation of CD4 T cells. It is unclear why two stimulatory ligands with overlapping roles have evolved. also bind regulatory molecule CTLA-4. We explored role in homeostasis proliferation CD4+FoxP3+ (Treg), which constitutively express high levels CTLA-4 yet critically dependent upon CD28 signals. observed that was dominant ligand Treg proliferation, survival, maintenance a...
Abstract CTLA‐4 and PD‐1 are key immune checkpoint receptors that targeted in the treatment of cancer. A recently identified physical interaction between respective ligands, CD80 PD‐L1, has been shown to block PD‐L1/PD‐1 binding prevent PD‐L1 inhibitory functions. Since is known capture degrade its ligands via transendocytosis, we investigated interplay transendocytosis CD80/PD‐L1 interaction. We find results a time‐dependent recovery availability correlates with removal. Moreover, highly...
Heterozygous mutations in CTLA-4 result an inborn error of immunity with autoimmune and frequently severe clinical phenotype. Autologous T cell gene therapy may offer a cure without the immunological complications allogeneic hematopoietic stem transplantation. Here, we designed homology-directed repair (HDR) editing strategy that inserts cDNA into first intron genomic locus primary human cells. This resulted regulated expression CD4 + cells, functional studies demonstrated CD80 CD86...
Germinal center (GC) dysregulation has been widely reported in the context of autoimmunity. Here, we show that interleukin 21 (IL-21), archetypal follicular helper T cell (Tfh) cytokine, shapes scale and polarization spontaneous chronic autoimmune as well transient immunization-induced GC. We find IL-21 receptor deficiency results smaller GC are profoundly skewed toward a light zone B phenotype plays key role selection cells for entry to dark zone. Light skewing previously mice lacking cycle...
CTLA-4 is an essential regulator of T-cell immune responses whose intracellular trafficking a hallmark its expression. Defects in due to LRBA deficiency cause profound autoimmunity humans. rapidly internalizes via clathrin-dependent pathway followed by poorly characterized recycling and degradation fates. Here, we explore the impact manipulating Rab GTPases on expression determine how these proteins affect trafficking. We observe that distributed across several compartments marked Rab5, Rab7...
We report the discovery of spiro[cyclohexane-pyrano[3,4-b]indole]-amines, as functional nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonists with strong efficacy in preclinical models acute neuropathic pain. Utilizing 4-(dimethylamino)-4-phenylcyclo-hexanone 1 tryptophol an oxa-Pictet–Spengler reaction led to formation spiroether 2, representing a novel NOP agonistic chemotype. This finding initially stems from systematic derivatization 1, which resulted alcohols 3–5, ethers 6...
In an adult human body, only a minority (~1%) of cells are dividing; all others either quiescent, senescent or terminally differentiated. Cellular quiescence, also called G0, is reversible non-proliferative state in which cells, such as stem exist until stimuli trigger their re-entry into the cell cycle. Quiescent known to reside within microenvironment niches specific extracellular matrix (ECM) composition, but molecular mechanisms that control entry and maintenance G0 long-term survival...
Several derivatives of 3,4-diaryl- and 3,4-diindolylpyrrole-2,5-dicarboxylic acids including lycogalic acid A two Halomonas metabolites were synthesized by oxidative dimerization arylpyruvic or arylpyruvates in the presence ammonia. The reaction can be applied for a short synthesis lukianol A.
The reaction of an N-protected 3-bromo-4-(indol-3-yl)maleimide with methyl (2-nitrophenyl)acetates in the presence base affords condensed cycloheptatriene derivatives which can be transformed into arcyriacyanin-type alkaloids. unusual sequence implies a heptatrienyl–cycloheptadienyl anion rearrangement followed by 1,5-sigmatropic shift to yield thermodynamically more stable derivative.
Abstract The CTLA-4 and PD-1 checkpoints control immune responses to self-antigens are key targets in cancer immunotherapy. Both pathways connected via a cis interaction between CD80 PD-L1, the ligands for respectively. This prevents binding PD-L1 but is reversed by trans-endocytosis of CD80. However, mechanism which selectively removes not unclear. Here we show that – interactions unimpeded with does displace per se. Rather, both rigidity bivalency WT molecule required orientate such no...
The CTLA-4 and PD-1 checkpoints control immune responses to self-antigens andare key targets in cancer immunotherapy. Both pathways are connected via a cisinteraction between CD80 PD-L1, the ligands for respectively.This cis interaction prevents binding PD-L1 but is reversed by transendocytosisof CD80. However, mechanism which selectively removesCD80 not unclear. Here we show that – interactions areunimpeded with does displace PD-L1per se. Rather, both rigidity bivalency of WT molecule...
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