A5083824953- RNA modifications and cancer
- Mycobacterium research and diagnosis
- Tuberculosis Research and Epidemiology
- Cancer-related gene regulation
- RNA and protein synthesis mechanisms
- Enzyme Structure and Function
- Biochemical and Molecular Research
- Neurological diseases and metabolism
- Microbial Metabolism and Applications
- Microbial Natural Products and Biosynthesis
- Synthesis and Reactions of Organic Compounds
- Protein Structure and Dynamics
- vaccines and immunoinformatics approaches
- Analytical Chemistry and Chromatography
- Computational Drug Discovery Methods
- Synthesis and Characterization of Heterocyclic Compounds
- SARS-CoV-2 and COVID-19 Research
- Microwave-Assisted Synthesis and Applications
- Mass Spectrometry Techniques and Applications
- Photosynthetic Processes and Mechanisms
- Metabolomics and Mass Spectrometry Studies
- Synthesis and biological activity
- Diagnosis and treatment of tuberculosis
- HIV/AIDS drug development and treatment
- Cancer Research and Treatments
University of Cambridge
2011-2024
Reactive oxygen species (ROS)-mediated oxidative stress and DNA damage have recently been recognized as contributing to the efficacy of most bactericidal antibiotics, irrespective their primary macromolecular targets. Inhibitors targets involved in both combating well being required for vivo survival may exhibit powerful synergistic action. This study demonstrates that de novo arginine biosynthetic pathway Mycobacterium tuberculosis (Mtb) is up-regulated early response stress-elevating agent...
Abstract The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has a central role in non-homologous end joining, one of the two main pathways that detect and repair DNA double-strand breaks (DSBs) humans 1,2 . DNA-PKcs is great importance repairing pathological DSBs, making inhibitors attractive therapeutic agents for cancer combination with DSB-inducing radiotherapy chemotherapy 3 Many selective have been developed exhibit potential as treatment various cancers 4 Here we report...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly growing infectious disease, widely spread with high mortality rates. Since the release of SARS-CoV-2 genome sequence in March 2020, there has been an international focus on developing target-based drug discovery, which also requires knowledge 3D structure proteome. Where are no experimentally solved structures, our group created models coverage 97.5% and characterized them using state-of-the-art computational...
Structure-guided drug discovery emerged in the 1970s and 1980s, stimulated by three-dimensional structures of protein targets that became available, mainly through X-ray crystal structure analysis, assisted development synchrotron radiation sources. Structures known drugs or inhibitors were used to guide leads. The growth high-throughput screening during late 1980s early 1990s pharmaceutical industry chemical libraries hundreds thousands compounds molecular weight approximately 500 Da was...
Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria that has emerged as threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, treat result in accelerated function decline premature death. There therefore an urgent need develop novel antibiotics improved efficacy. tRNA (m1G37) methyltransferase (TrmD) promising target for antibiotics. It...
The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion L-glutamate to L-arginine. Arginine auxotrophs (argB/argF deletion mutants) Mycobacterium tuberculosis are rapidly sterilised in mice, while inhibition ArgJ with Pranlukast was found clear chronic M. infection a mouse model. Enzymes arginine biosynthetic have therefore emerged as promising targets for anti-tuberculosis drug discovery. In this work, ligandability four ArgB, ArgC, ArgD and ArgF is...
The serpinopathies result from point mutations in members of the serine protease inhibitor or serpin superfamily. They are characterized by formation ordered polymers that retained within cell synthesis. This causes disease a "toxic gain function" accumulated protein and "loss as deficiency inhibitors control important proteolytic cascades. exemplified Z (Glu342Lys) mutant α₁-antitrypsin results retention endoplasmic reticulum hepatocytes. These form intracellular inclusions associated with...
Abstract Translational frameshift errors are often deleterious to the synthesis of functional proteins and could therefore be promoted therapeutically kill bacteria. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 reading frame during protein translation represents attractive potential target for development new antibiotics. Here, we describe application a structure-guided fragment-based drug discovery approach design class...
Mycobacterium abscessus (Mab) has emerged as a challenging threat to individuals with cystic fibrosis. Infections caused by this pathogen are often impossible treat due the intrinsic antibiotic resistance leading lung malfunction and eventually death. Therefore, there is an urgent need develop new drugs against novel targets in Mab overcome drug subsequent treatment failure. In study, SAICAR synthetase (PurC) from was identified promising target for antibiotics. An in-house fragment library...
The interaction between <italic>Mycobacterium tuberculosis</italic> EthR and its operator DNA has been studied by native mass spectrometry, revealing an interesting stoichiometry.
Abstract Native nanoelectrospray ionization mass spectrometry is an underutilized technique for fragment screening. In this study, the first demonstration provided of use native screening fragments against a protein–DNA interaction. EthR transcriptional repressor EthA expression in Mycobacterium tuberculosis (Mtb) that reduces efficacy ethionamide, second‐line antitubercular drug used to combat multidrug‐resistant Mtb strains. A small‐scale campaign was conducted EthR–DNA interaction using...
Anti-microbial resistance is a rising global healthcare concern that needs urgent attention as growing number of infections become difficult to treat with the currently available antibiotics. This particularly true for mycobacterial like tuberculosis and leprosy those emerging opportunistic pathogens such Mycobacterium abscessus , where multi-drug leads increased cost mortality. M. highly drug-resistant non-tuberculous mycobacterium which causes life-threatening in people chronic lung...
Abstract Ligand binding hotspots are regions of protein surfaces that form particularly favourable interactions with small molecule pharmacophores. Targeting these maximises the efficiency ligand binding. Existing methods capable identifying but often lack assays to quantify and direct elaboration at sites. Herein, we describe a fragment‐based competitive 19 F Based NMR (LB‐NMR) screening platform enables routine, quantitative profiling focused ligand‐binding hotspots. As proof concept,...
Summary Viruses often encode proteins that mimic host in order to facilitate infection. Little work has been done understand the potential mimicry of SARS-CoV-2, SARS-CoV, and MERS-CoV spike proteins, particularly receptor-binding motifs, which could be important determining tropism virus. Here, we use structural bioinformatics software characterize three coronavirus protein motifs. We utilize sequence-independent alignment tools compare structurally known or predicted three-dimensional...
Abstract Native nanoelectrospray ionization mass spectrometry is an underutilized technique for fragment screening. In this study, the first demonstration provided of use native screening fragments against a protein–DNA interaction. EthR transcriptional repressor EthA expression in Mycobacterium tuberculosis (Mtb) that reduces efficacy ethionamide, second‐line antitubercular drug used to combat multidrug‐resistant Mtb strains. A small‐scale campaign was conducted EthR–DNA interaction using...
Abstract Plants have evolved sophisticated mechanisms to adapt temperature fluctuations, including transcriptional, post-transcriptional, and post-translational processes. Recent discoveries highlight RNA ThermoSwitches, cis-acting elements in several plant mRNAs that regulate protein synthesis based on changes. These mechanisms, first identified Arabidopsis thaliana, offer a promising tool for biotechnology by enabling temperature-sensitive control of expression. This study demonstrates,...
Abstract Mycobacterium abscessus (Mab) is a rapidly growing multidrug-resistant species among nontuberculous mycobacteria (NTM). Pulmonary infections caused by M. are difficult to treat and often result in an accelerated condition premature death of immunosuppressed patients such as those with cystic fibrosis, putting them at greater risk other increasing the urgency developing novel class antibiotics. Here, we explore use toxin antitoxin (TA) interesting promising new target fragment-based...
Abstract Ligand binding hotspots are regions of protein surfaces that form particularly favourable interactions with small molecule pharmacophores. Targeting these maximises the efficiency ligand binding. Existing methods capable identifying but often lack assays to quantify and direct elaboration at sites. Herein, we describe a fragment‐based competitive 19 F Based NMR (LB‐NMR) screening platform enables routine, quantitative profiling focused ligand‐binding hotspots. As proof concept,...