A5018229742- Influenza Virus Research Studies
- Diabetes and associated disorders
- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- HIV/AIDS drug development and treatment
- Animal Virus Infections Studies
- Chemical Synthesis and Analysis
- Pneumocystis jirovecii pneumonia detection and treatment
- Trypanosoma species research and implications
- Drug Transport and Resistance Mechanisms
- Computational Drug Discovery Methods
- Hemoglobin structure and function
- Malaria Research and Control
- Complement system in diseases
- Protein Structure and Dynamics
- Liver Disease Diagnosis and Treatment
- Immune Cell Function and Interaction
- DNA and Nucleic Acid Chemistry
- Metabolism and Genetic Disorders
- Immune Response and Inflammation
- Protein purification and stability
- Radiopharmaceutical Chemistry and Applications
- Hepatitis B Virus Studies
- RNA and protein synthesis mechanisms
- Viral Infections and Vectors
LifeArc
2015-2023
Stevenage Bioscience Catalyst
2017
The Francis Crick Institute
2013-2014
Imperial College London
2006-2009
University of Oxford
2005-2006
The hemagglutinin (HA) of influenza A(H3N2) virus responsible for the 1968 pandemic derived from an avian virus. On introduction into humans, its receptor binding properties had changed a preference receptors (α2,3-linked sialic acid) to human (α2,6-linked acid). By 2001, avidity H3 viruses declined, and since then affinity has also decreased significantly. These changes in binding, which correlate with increased difficulties propagation vitro antigenic analysis, have been assessed by...
The viruses that caused the three influenza pandemics of twentieth century in 1918, 1957, and 1968 had distinct hemagglutinin receptor binding glycoproteins evolved capacity to recognize human cell receptors. We have determined structure H2 from second pandemic, "Asian Influenza" 1957. compare it with 1918 "Spanish hemagglutinin, H1, "Hong Kong H3, show despite its close overall structural similarity more distant relationship site is closely related H3 hemagglutinin. By analyzing...
Profiling of the four known galactose-binding receptors in C‐type lectin family has been undertaken parallel on a glycan array. The results are generally consistent with those previous assays using various different formats, but they provide direct comparison properties receptors, revealing that fall into two distinct groups. major subunit rat asialoglycoprotein receptor and Kupffer cell show similar broad preferences for GalNAc-terminated glycans, while macrophage galactose human scavenger...
To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has IC
Restriction factors (RFs) form important components of host defenses to retroviral infection. The Fv1, Trim5α, and TrimCyp RFs contain N-terminal dimerization C-terminal specificity domains that target assembled capsid (CA) proteins enclosing the viral core. However, molecular detail interaction between their CA targets is unknown. Therefore, we have determined crystal structure B-box coiled-coil (BCC) region from Trim5α used small-angle X-ray scattering examine solution BCC, domain Fv1...
The scavenger receptor C-type lectin (SRCL) is an endothelial that similar in organization to type A receptors for modified low density lipoproteins but contains a carbohydrate-recognition domain (CRD). Fragments of the consisting entire extracellular and CRD have been expressed characterized. trimer held together by collagen-like coiled-coil domains adjacent CRD. amino acid sequence very asialoglycoprotein other galactose-specific receptors, SRCL binds selectively asialo-orosomucoid rather...
The mitotic kinase Aurora-A and its partner protein TPX2 (Targeting Protein for Xenopus kinesin-like 2) are overexpressed in cancers, it has been proposed that they work together as an oncogenic holoenzyme. is responsible activating during mitosis, ensuring proper cell division. Disruption of the interface with therefore a potential target novel anticancer drugs exploit increased sensitivity cancer cells to stress. Here, we investigate using coprecipitation assays isothermal titration...
As avian influenza A(H5N1) viruses continue to circulate in Asia and Africa, global concerns of an imminent pandemic persist. Recent experimental studies suggest that efficient transmission between humans current H5N1 only requires a few genetic changes. An essential step is alteration the virus hemagglutinin from preferential binding receptors for recognition human present upper airway. We have identified receptor-binding changes which emerged during infection humans, due single amino acid...
Mutant H5N1 influenza viruses have been isolated from humans that increased human receptor avidity. We compared the binding properties of these mutants with those wild-type viruses, and determined structures their haemagglutinins in complex analogues. Mutants Vietnam bind tighter to by acquiring basic residues near site. They more weakly avian because they lack specific interactions between Asn-186 Gln-226. In contrast, a double mutant, Δ133/Ile155Thr, Egypt has greater avidity for while...
Engineered receptor fragments and glycoprotein ligands employed in different assay formats have been used to dissect the basis for dramatic enhancement of binding two model membrane receptors, dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) macrophage galactose lectin, compared simple sugars. These approaches make it possible quantify importance major factors that combine enhance affinity single carbohydrate-recognition domains (CRDs) by 100-to...
Significance The protease MALT1 has been shown to play an essential role in the adaptive immune response and development of lymphoma. catalytic activity is tightly regulated by monoubiquitination, however, how ubiquitin conjugated manner which this modification regulates remains poorly understood. Our data suggest that Ig3 domain physically recruits enable monoubiquitination conjugation activates inducing conformational changes are communicated active site. These findings identify as a novel...
Development of a class bicyclic inhibitors the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG), starting from known compounds with activity against related parasite PKG orthologue, is reported. Examination key sub-structural elements led to new good levels inhibitory recombinant and in vitro parasite. Key examples were shown possess encouraging ADME properties, computational analysis provided valuable insight into origins observed profiles.
Focussed studies on imidazopyridine inhibitors of Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG) have significantly advanced the series towards desirable in vitro property space. LLE-based approaches combining improvements cell potency, key physicochemical parameters and structural novelty are described, a structure-based design hypothesis relating to substituent regiochemistry has directed efforts examples with well-balanced ADME selectivity profiles.
Programmed death-ligand 1 (PD-L1) is a key immune regulatory protein that interacts with programmed cell death (PD-1), leading to T-cell suppression. Whilst this interaction in self-tolerance, cancer cells evade the system by overexpressing PD-L1. Inhibition of PD-1/PD-L1 pathway standard monoclonal antibodies has proven highly effective treatment; however, single domain (VHH) may offer numerous potential benefits. Here, we report identification and characterization diverse panel 16 novel...
We present the synthesis and application of a molecule containing both powerful influenza neuraminidase (NA) inhibitor phospha-oseltamivir d-biotin, connected via an undecaethylene glycol spacer. It inhibits virus (from H3N2 X31 virus) in same range as oseltamivir, with slow off-rate, produces stable NA-coated surface when loaded onto streptavidin-coated biosensors. Purified binds to these biosensors apparent dissociation constant low picomolar binding antibodies immobilized could be readily...
The post-transcriptional modifier tRNA-(N1G37) methyltransferase (TrmD) has been proposed to be essential for growth in many Gram-negative and Gram-positive pathogens, however previously reported inhibitors show only weak antibacterial activity. In this work, optimisation of fragment hits resulted compounds with low nanomolar TrmD inhibition incorporating features designed enhance bacterial permeability covering a range physicochemical space. resulting lack significant activity suggests that...